KR100830902B1 - Dipeptidyl Peptidase-IV Inhibiting Compounds, Methods of Preparing the Same, and Pharmaceutical Compositions Containing the Same as an Active Agent - Google Patents

Abstract

The present invention relates to a novel compound exhibiting excellent inhibitory activity against Dipeptidyl Peptidase-IV (DPP-IV), a preparation method thereof, and a pharmaceutical composition containing the same as an active ingredient.

Description

Dipeptidyl Peptidase-IV Inhibiting Compounds, Methods of Preparing the Same, and Pharmaceutical Compositions Containing the Same as an Active Agent}

The present invention relates to a novel compound exhibiting excellent inhibitory activity against Dipeptidyl Peptidase-IV (DPP-IV), a preparation method thereof, and a pharmaceutical composition containing the same as an active ingredient.

Diabetes has many adverse effects on people's health and causes many complications. Diabetes is classified as type 1 due to the insufficiency of insulin due to the destruction of the pancreatic cells, and type 2 due to the fact that insulin is not produced or does not respond to insulin due to other conditions. Occupies. Representative complications of diabetes include hyperlipidemia, hypertension, retinopathy, renal failure and the like (Paul Zimmer, et al., Nature, 2001, 414, 782). As a treatment for diabetes, sulfonylureas (promoting insulin secretion in pancreatic cells), biguananides (inhibition of glucose production in the liver), α-Glucosidase inhibitors (inhibition of glucose uptake in the intestine), etc. have been used recently. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists (Thiazolidinediones, increasing insulin sensitivity) are in the spotlight. However, these drugs have side effects due to their mechanisms such as hypoglycemia and weight gain (David E. Moller, Nature, 2001, 414, 821). Therefore, there is an urgent need for the development of anti-diabetic agents that have fewer side effects and do not cause hypoglycemia and weight gain.

Recently, rats from which the Dipeptidyl Peptidase-IV (DPP-IV) gene has been removed have been found to maintain the activity of Glucagon-like Protein 1 (GLP-1) and reduce blood sugar by increasing the amount of insulin, suggesting the possibility of treating diabetes. (Mar guet D. et al, Proc. Natl. Acad. Sci. USA, (2000) 97, 6874-6879). GLP-1 plays an important role in differentiating and growing pancreatic cells β-cells in vivo and producing and secreting insulin. This GLP-1 is inactivated by DPP-IV, and DPP-IV inhibitors have been reported to enhance insulin secretion by inhibiting this mechanism. In addition, since GLP-1 plays a role in making rats feel full and lose weight by slowing digestion of food in the intestine, DPP-IV inhibitors have also been developed as obesity treatments. Recently, several researchers have shown that DPP-IV inhibitors improve glucose and lipids in animal experiments (Pospislik J. A., et al, Diabetes, (2002) 51, 943-950). Therefore, it can be said that DPP-IV inhibitor is very important as a therapeutic agent for diabetes.

The research on DPP-IV inhibitors has focused mainly on substances in which cyano groups are substituted in the pyrrolidine ring. For example, WO 00/34241 discloses DPP-IV inhibitors represented by the formula:

(Wherein R is a substituted adamantyl group and n is 0 to 3)

Examples of further inhibitors include WO 04/064778, WO 03/004498, WO 03/082817 and the like, and WO 04/064778 discloses DPP-IV inhibitors represented by the following formulas.

Wherein Ar is an unsubstituted or substituted phenyl group and R ₁₅ , R ₁₆ and R ₁₇ Is hydrogen or alkyl, and U, V and W each represent nitrogen, oxygen, substituted nitrogen or carbon)

WO 03/004498 also discloses DPP-IV inhibitors represented by the formula:

Wherein Ar is an unsubstituted or substituted phenyl group, R ₁₈ Is hydrogen or alkyl, and T represents nitrogen or substituted carbon)

WO 03/082817 also discloses DPP-IV inhibitors represented by the formula:

Wherein Ar is an unsubstituted or substituted phenyl group and R ₁₉ , R ₂₀ and R ₂₁ Is hydrogen or alkyl, and Q represents nitrogen or substituted carbon)

The compounds as DPP-IV inhibitors are similar to the present invention in that they are amide-linked cyclic compounds, but the substituted phenyl group represented by Ar in the above formulas may be a 5 or 6 saturated or unsaturated cyclic compound of the present invention. It is completely different from the substituted form, and there is no known DPP-IV inhibitor of the structure in which the lactam ring is substituted at the phenyl position according to the present invention and a method for producing the same.

After continuing in-depth research and various experiments, the inventors have confirmed that the DPP-IV inhibitor compounds, represented by optionally substituted lactam rings, are effective as DPP-IV inhibitors, as described below. Completed on the basis of

Specifically, the first object of the present invention is to provide a DPP-IV inhibitor compound represented by an optionally substituted lactam ring.

It is a second object of the present invention to provide a method for preparing the compound.

It is a third object of the present invention to provide a pharmaceutical composition comprising the compound and a method for treating or preventing a disease caused by DPP-IV using an effective amount of the compound.

To achieve this object, a dipeptidyl peptidase-IV (DPP-IV) inhibitor compound according to the present invention is represented by the following formula (1).

(1)

(One)

In the above formula,

(A) A is selected from substituents of the formulas (2) to (7);

(2)(Ⅰ)

(2)

In which R ₁ Is hydrogen or substituted or unsubstituted C ₁ -C ₄ alkyl; X is carbon or nitrogen;

(3)(Ii)

(3)

In which R ₂ Is hydrogen or substituted or unsubstituted C ₁ -C ₄ alkyl;

(4)(Ⅲ)

(4)

(5)(Ⅳ)

(5)

In which R ₃ is hydrogen or substituted or unsubstituted alkyl, cycloalkyl, aryl or heteroaryl; R ' ₃ Is hydrogen, CF ₃ ;

(6)(Ⅴ)

(6)

In which R ₄ Is hydrogen, halogen, or substituted or unsubstituted C ₁ -C ₄ Alkyl or selected from substituents of formulas 6a and 6b;

(6a)

(6a)

(6b)

(6b)

In the above formulas, R ₅ Is hydrogen, halogen, or substituted or unsubstituted C ₁ -C ₄ Alkyl, X is oxygen, sulfur, or a sulfone group;

(7)(Ⅵ)

(7)

In which R ₆ Is halogen or substituted or unsubstituted C ₁ -C ₄ Alkyl;

(B) B is selected from substituents of the formulas (8) to (11);

(8)(Ⅰ)

(8)

Wherein R ₇ , R ₈ , R ₉ and R ₁₀ Are each independently hydrogen, halogen, or substituted or unsubstituted C ₁ -C ₄ alkyl;

(9)(Ii)

(9)

Wherein R ₁₁ , R ₁₂ and R ₁₃ Are each independently hydrogen, halogen, or substituted or unsubstituted C ₁ -C ₄ alkyl; Y is oxygen, sulfur or SO ₂ ;

(10)(Ⅲ)

10

Wherein R ₁₄ and R ₁₅ Are each independently hydrogen, halogen, or substituted or unsubstituted C ₁ -C ₄ alkyl; Z is -CH- or oxygen and R ₁₄ is nothing when Z is oxygen;

(11)(Ⅳ)

(11)

In which R ₁₇ Is substituted or unsubstituted C ₁ -C ₄ alkyl.

When C ₁ -C ₄ alkyl is substituted in the above formulas, it may be preferably alkyl substituted with halogen, and particularly preferably alkyl substituted with fluorine.

In Formula 5, R ₃ may be preferably selected from the following substituents.

(Iii) hydrogen;

(Ii) substituted or unsubstituted C ₁ -C ₄ alkyl;

(Iii) Formula -CH ₂ -R ₁₈ , wherein R ₁₈ is C ₁ -C ₄ alkoxyalkyl, or C ₃ -C ₇ cycloalkyl unsubstituted or substituted with halogen or hydroxy, or substituted with halogen or hydroxy Phenyl;

(Iii) substituted or unsubstituted C ₃ -C ₇ cycloalkyl;

, 여기서 R₁₉ 및 R₂₀ 는 각각 독립적으로 수소, 할로겐, 또는 치환 또는 비치환된 C₁-C₄ 알킬기이며; 및(Ⅴ) expression

, Where R ₁₉ And R ₂₀ Are each independently hydrogen, halogen, or a substituted or unsubstituted C ₁ -C ₄ alkyl group; And

(Iii) 5- or 6-membered heteroaryl unsubstituted or substituted with halogen or hydroxy.

C ₃ -C ₇ cycloalkyl and C ₁ -C _{4 above} When alkyl is substituted, cycloalkyl and alkyl substituted with halogen or hydroxy are preferred.

Preferred examples of the heteroaryl include 2-furan, 3-furan, 2-thiophene, 3-thiophene, 2-pyridine, 3-pyridine, 4-pyridine, 2-pyrrole, 3-pyrrole and the like. And they may be in a substituted form as defined above.

The compounds of the present invention include their isomers, and among those isomers NH₂Preferred is a compound in which the carbon substituted with forms a stereogenic center having a structure as shown in the following Chemical Formula 1a.

(1a)

(1a)

Wherein A and B are the same as defined in Chemical Formula 1.

The compounds of the present invention may form addition salts with pharmaceutically acceptable acids. "Pharmaceutically acceptable salts" of the present invention include inorganic acid salts, organic acid salts, amino acid salts, and the like, and specific examples thereof include salts with inorganic acids such as hydrochloric acid, bromic acid, phosphoric acid and sulfuric acid, acetic acid and trifluorine. Organic carboxylic acids such as roacetic acid, citric acid, formic acid, maleic acid, fish acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, manderinic acid, ascorbic acid, dried acid or salts with methanesulfonic acid, para-toluenesulfonic acid, and the like. have. These acid addition salts, based on the structure of Formula 1, can be prepared by a known technique.

The compounds of the present invention or pharmaceutically acceptable salts thereof may be present in the form of hydrates or solvates.

Particularly preferred examples of the compounds of formula 1 according to the present invention include, but are not limited to the following.

3- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -oxazolidin-2-one;

3- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -5-methyl-oxazolidin-2-one;

1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -piperidin-2-one;

1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -4-methyl-pyrrolidin-2-one;

1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -4,4-dimethyl-pyrrolidin-2-one;

1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -3-fluoro-pyrrolidin-2-one;

1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3- a ] pyrazine-7- Yl) -butyl] -pyrrolidin-2-one;

1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl]-3-fluoro-piperidin-2-one;

1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -4-methyl-1,5-dihydro-pyrrole-2-one;

1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -4-methyl-piperidin-2-one;

1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -5,5-difluoro-piperidin-2-one;

1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -5R-methyl-piperidin-2-one;

1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -4-trifluoromethyl-pyrrolidin-2-one;

1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -4-trifluoromethyl-piperidin-2-one;

1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -5-trifluoromethyl-piperidin-2-one;

4- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -6-methyl-morpholin-3-one;

1- [2S-amino-4- (3,4-dihydro-1H-isoquinolin-2-yl) -4-oxo-butyl] -piperidin-2-one;

1- [2S-amino-4- (3,4-dihydro-1H-isoquinolin-2-yl) -4-oxo-butyl] -4-methyl-pyrrolidin-2-one;

1- [2S-amino-4-oxo-4- (3-trifluoromethyl-4,5-dihydro-7H-isoxazolo [3,4- c ] pyridin-6-yl) butyl] -pi Ferridin-2-one;

1- [2S-amino-4-oxo-4- (3-trifluoromethyl-1,4,5,7-tetrahydro-pyrazolo [3,4- c ] pyridin-6-yl) -butyl] -Piperidin-2-one;

1- [2S-amino-4-oxo-4- (4-trifluoromethyl-5,8-dihydro-6 H -pyrido [3,4-d] pyrimidin-7-yl) -butyl] -5R-methyl-1-piperidin-2-one;

(5R) -1-{(2S) -2-amino-4-oxo-4- [2-phenyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] Pyrimidin-7 (6H) -yl] butyl} -5-methylpiperidin-2-one;

(6S) -4-{(2S) -2-amino-4-oxo-4- [2-phenyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] Pyrimidin-7 (6H) -yl] butyl} -6-methylmorpholin-3-one; .

1-{(2S) -2-amino-4-oxo-4- [2-phenyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 (6H) -yl] butyl} -5,5-difluoropiperidin-2-one;

1-{(2S) -2-amino-4- [2-cyclopropyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 (6H) -Yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

1-{(2S) -2-amino-4- [2-cyclopropyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 (6H) -Yl] -4-oxobutyl} -5-methylpiperidin-2-one;

(6S) -4-{(2S) -2-amino-4- [2-cyclopropyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine- 7 (6H) -yl] -4-oxobutyl} -6-methylmorpholin-3-one;

1-{(2S) -2-amino-4-oxo-4- [5- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl] butyl} -5,5 -Difluoropiperidin-2-one;

(6S) -4-{(2S) -2-amino-4-oxo-4- [5- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl] butyl} -6-methylmorpholin-3-one;

1-{(2S) -2-amino-4- [2- (4-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

(6S) -4-{(2S) -2-amino-4- [2- (4-fluorophenyl) -4- (trifluoromethyl) -5,8-di hydropyrido [3,4- d] pyrimidin-7 (6H) -yl] -4-oxobutyl} -6-methylmorpholin-2-one;

1-{(2S) -2-amino-4- [2- (3-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

(6S) -4-{(2S) -2-amino-4- [2- (3-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d] pyrimidin-7 (6H) -yl] -4-oxobutyl} -6-methylmorpholin-3-one;

(5R) -1-{(2S) -2-amino-4- [2- (4-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d] pyrimidin-7 (6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one;

1-{(2S) -2-amino-4- [2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d ] Pyrimidin-7 (6H) -yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

(6S) -4-{(2S) -2-amino-4- [2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3 , 4-d] pyrimidin-7 (6H) -yl] -4-oxobutyl} -6-methylmorpholin-3-one;

(5R) -1-{(2S) -2-amino-4- [2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3 , 4-d] pyrimidin-7 (6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one;

(5R) -1-{(2S) -2-amino-4- [2-cyclopentyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine- 7 (6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one;

(6S) -4-{(2S) -2-amino-4- [2-cyclopentyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine- 7 (6H) -yl] -4-oxobutyl} -6-methylmorpholin-3-one;

1-{(2S) -2-amino-4- [2-cyclopentyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 (6H) -Yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

(5R) -1-[(2S) -2-amino-4-oxo-4- {2- [4- (trifluoromethyl) phenyl] -6,7-dihydro [1,3] thiazolo [ 4,5, c] pyridin-5 (4H) -yl} butyl] -5-methylpiperidin-2-one;

(6S) -4-[(2S) -2-amino-4-oxo-4- {2- [4- (trifluoromethyl) phenyl] -6,7-dihydro [1,3] thiazolo [ 4,5, c] pyridin-5 (4H) -yl} butyl] -6-methylmorpholin-3-one;

1-[(2S) -2-amino-4-oxo-4- {2- [4- (trifluoromethyl) phenyl] -6,7-dihydro [1,3] thiazolo [4,5, c] pyridin-5 (4H) -yl} butyl] -5,5-difluoropiperidin-2-one;

(5R) -1-{(2S) -2-amino-4- [2- (4-fluorophenyl) -6,7-dihydro [1,3] thiazolo [4,5, c] pyridine- 5 (4H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one;

(6S) -4-{(2S) -2-amino-4-oxo-4- [2- (4-fluorophenyl) 6,7-dihydro [1,3] thiazolo [4,5, c ] Pyridin-5 (4H) -yl] butyl} -6-methylmorpholin-3-one;

1-{(2S) -2-amino-4- [2- (4-fluorophenyl) -6,7-dihydro [1,3] thiazolo [4,5, c] pyridine-5 (4H) -Yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

(5R) -1-{(2S) -2-amino-4-oxo-4- [2- (tetrahydro-2H-pyran-4-yl) -6,7-dihydro [1,3] thiazolo [4,5, c] pyridin-5 (4H) -yl] butyl} -5-methylpiperidin-2-one;

(6S) -4-{(2R) -2-amino-4-oxo-4- [2- (tetrahydro-2H-pyran-4-yl) -6,7-dihydro [1,3] thiazolo [4,5, c] pyridin-5 (4H) -yl] butyl} -6-methylmorpholin-3-one;

1-{(2S) -2-amino-4-oxo-4- [2- (tetrahydro-2H-pyran-4-yl) -6,7-dihydro [1,3] thiazolo [4,5 , c] pyridin-5 (4H) -yl] butyl} -5,5-difluoropiperidin-2-one;

(6S) -4-{(2S) -2-amino-4-oxo-4- [2- (trifluoromethyl) -6,7-dihydro [1,3] thiazolo [4,5, c ] Pyridin-5 (4H) -yl] butyl} -6-methylmorpholin-3-one;

1-{(2S) -2-amino-4-oxo-4- [2- (trifluoromethyl) -6,7-dihydro [1,3] thiazolo [4,5, c] pyridine-5 (4H) -yl] butyl} -5,5-difluoropiperidin-2-one;

(5R) -1-{(2S) -2-amino-4- [2- (2-methoxyethyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d] pyrimidin-7 (6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one;

1-{(2S) -2-amino-4- [2- (2-methoxyethyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

(5R) -1-{(2S) -2-amino-4- [2- (cyclopropylmethyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] Pyrimidin-7 (6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one;

1-{(2S) -2-amino-4- [2- (cyclopropylmethyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 (6H) -yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

(5R) -1-{(2S) -2-amino-4-oxo-4- [2-pyridin-4-yl-4- (trifluoromethyl) -5,8-dihydropyrido [3, 4-d] pyrimidin-7 (6H) -yl] butyl} -5-methylpiperidin-2-one;

1-{(2S) -2-amino-4-oxo-4- [2-pyridin-4-yl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] Pyrimidin-7 (6H) -yl] butyl} -5,5-difluoropiperidin-2-one;

(5R) -1-{(2S) -2-amino-4- [2- (4-fluorobenzyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d] pyrimidin-7 (6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one;

1-{(2S) -2-amino-4- [2- (4-fluorobenzyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

(5R) -1-{(2S) -2-amino-4-oxo-4- [2- (3-thienyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3 , 4-d] pyrimidin-7 (6H) -yl] butyl} -5-methylpiperidin-2-one;

1-{(2S) -2-amino-4-oxo-4- [2- (3-thienyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d ] Pyrimidin-7 (6H) -yl] butyl} -5,5-difluoropiperidin-2-one;

(5R) -1-{(2S) -2-amino-4-oxo-4- [2- (2-thienyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3 , 4-d] pyrimidin-7 (6H) -yl] butyl} -5-methylpiperidin-2-one;

1-{(2S) -2-amino-4-oxo-4- [2- (2-thienyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d ] Pyrimidin-7 (6H) -yl] butyl} -5,5-difluoropiperidin-2-one;

(5R) -1-{(2S) -2-amino-4- [2- (2-furyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] Pyrimidin-7 (6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one;

1-{(2S) -2-amino-4- [2- (2-furyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 (6H) -yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

(5R) -1-{(2S) -2-amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] Pyrimidin-7 (6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one;

1-{(2S) -2-amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 (6H) -yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

(5R) -1-{(2S) -2-amino-4-oxo-4- [2- (1H-pyrrol-2-yl) -4- (trifluoromethyl) -5,8-dihydropyri Degree [3,4-d] pyrimidin-7 (6H) -yl] butyl} -5-methylpiperidin-2-one;

1-{(2S) -2-amino-4-oxo-4- [2- (1H-pyrrol-2-yl) -4- (trifluoromethyl) -5,8-dihydropyrido [3, 4-d] pyrimidin-7 (6H) -yl] butyl} -5,5-difluoropiperidin-2-one;

(5R) -1-{(2S) -2-amino-4-oxo-4- [2-pyridin-3-yl-4- (trifluoromethyl) -5,8-dihydropyrido [3, 4-d] pyrimidin-7 (6H) -yl] butyl} -5-methylpiperidin-2-one;

1-{(2S) -2-amino-4-oxo-4- [2-pyridin-3-yl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] Pyrimidin-7 (6H) -yl] butyl} -5,5-difluoropiperidin-2-one;

1-{(2S) -2-amino-4- [2-ethyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 (6H)- Il] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

(6S) -4-{(2S) -2-amino-4- [2-ethyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrimidine-7 (6H) -yl] -4-oxobutyl} -6-methylmorpholin-3-one;

1-{(2S) -2-amino-4- [2-isopropyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrimidine-7 (6H) -Yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

1-{(2S) -2-amino-4- [2-isopropyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 (6H) -Yl] -4-oxobutyl} -5-methylpiperidin-2-one;

(6S) -4-{(2S) -2-amino-4- [2-isopropyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine- 7 (6H) -yl] -4-oxobutyl} -6-methylmorpholin-3-one;

(6R) -4-{(2S) -2-amino-4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3 -a] pyrazin-7 (8H) -yl] butyl} -6-methylmorpholin-3-one;

(6S) -4-{(2S) -2-amino-4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3 -a] pyrazin-7 (8H) -yl] butyl} -6-methylmorpholin-3-one;

(5S) -1-{(2S) -2-amino-4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3 -a] pyrazin-7 (8H) -yl] butyl} -5-methylpiperidin-2-one;

(5S) -1-{(2S) -2-amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 ( 6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one;

(5R) -1-{(2S) -2-amino-4- [2-methyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 (6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one;

(5R) -1-{(2S) -2-amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrimidine-7 ( 6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one;

1-{(2S) -2-amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrimidin-7 (6H) -yl ] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

(6S) -4-{(2S) -2-amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 ( 6H) -yl] -4-oxobutyl} -6-methylmorpholin-3-one;

1-{(2S) -2-amino-4- [2-methyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrimidine-7 (6H)- Il] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

(6S) -4-{(2S) -2-amino-4- [2-methyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrimidine-7 (6H) -yl] -4-oxobutyl} -6-methylmorpholin-3-one;

1-{(2S) -2-amino-4-oxo-4- [4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrimidine-7 (6H)- Il] butyl} -5,5-difluoropiperidin-2-one;

(6S) -4-{(2S) -2-amino-4-oxo-4- [4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrimidine-7 (6H) -yl] butyl} -6-methylmorpholin-3-one;

1-{(2S) -2-amino-4-oxo-4- [3- (pentafluoroethyl) -5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazine -7 (8H) -yl] butyl} -5,5-difluoropiperidin-2-one;

(6S) -4-{(2S) -2-amino-4-oxo-4- [3- (pentafluoroethyl) -5,6-dihydro [1,2,4] triazolo [4,3 -a] pyrazin-7 (8H) -yl] butyl} -6-methylmorpholin-3-one;

4-{(2S) -2-amino-4- [2.4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrimidin-7 (6H) -yl]- 4-oxobutyl} -6-methylthiomorpholin-3-one;

1-{(2S) -2-amino-4- [2-t-butyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 (6H ) -Yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

(6S) -4-{(2S) -2-amino-4- [2-t-butyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrimidine -7 (6H) -yl] -4-oxobutyl} -6-methylmorpholin-3-one;

4-{(2S) -2-amino-4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazine -7 (8H) -yl] butyl} -6-methylthiomorpholin-3-one;

(5R) -1-{(2S) -2-amino-4- [2-ethyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrimidine-7 (6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one;

(5R) -1-{(2S) -2-amino-4-oxo-4- [2- (pentafluoroethyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3 , 4- d ] pyrimidin-7 (6H) -yl] butyl} -5-methylpiperidin-2-one;

(6S) -4-{(2S) -2-amino-4-oxo-4- [2- (pentafluoroethyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3 , 4- d ] pyrimidin-7 (6H) -yl] butyl} -6-methylmorpholin-3-one;

1-{(2S) -2-amino-4-oxo-4- [2- (pentafluoroethyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] Pyrimidin-7 (6H) -yl] butyl} -5,5-difluoropiperidin-2-one;

(5R) -1-{(2S) -2-amino-4-oxo-4- [2-propyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] Pyrimidin-7 (6H) -yl] butyl} -5-methylpiperidin-2-one;

1-{(2S) -2-amino-4-oxo-4- [2-propyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrimidine-7 (6H) -yl] butyl} -5,5-difluoropiperidin-2-one;

(5R) -1-{(2S) -2-amino-4- [2- (fluoromethyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] Pyrimidin-7 (6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one;

1-{(2S) -2-amino-4- [2- (fluoromethyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 (6H) -yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one;

1-{(2S) -2-amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl ] -4-oxobutyl} -4-methyl-1,5-dihydro-2H-pyrrol-2-one;

1-{(2S) -2-amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 (6H) -yl] -4-oxobutyl} -4-methyl-1,5-dihydro-2H-pyrrol-2-one;

1-{(2S) -2-amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl ] -4-oxobutyl} -4-methyloxopyrrolidin-2-one;

1-{(2S) -2-amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 (6H) -yl] -4-oxobutyl} -4-methylpyrrolidin-2-one;

1-{(2S) -2-amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl ] -4-oxobutyl} -5- (trifluoromethyl) piperidin-2-one;

1-{(2S) -2-amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl ] -4-oxobutyl} -4- (trifluoromethyl) pyrrolidin-2-one;

1-{(2S) -2-amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 (6H) -yl] -4-oxobutyl} -4- (trifluoromethyl) pyrrolidin-2-one;

1-{(2S) -2-amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl ] -4-oxobutyl} -4-methyloxopiperidin-2-one;

1-{(2S) -2-amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 (6H) -yl] -4-oxobutyl} -4-methylpiperidin-2-one;

(5R) -1-{(2S) -2-amino-4- [2-cyclobutyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine- 7 (6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one;

1-{(2S) -2-amino-4- [2-cyclobutyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 (6H) -Yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one.

The present invention also relates to a method for preparing the compound of Formula 1.

The first exemplary method of preparing the compound of Formula 1 includes reacting a compound of Formula 12 with a compound of Formula 13 and then removing the amine protecting group P ₁ .

(12)

(12)

R ₂₁ NH ₂ G ₁ (13)

In the above formula,

R ₂₁ Is selected from substituents of the formulas 13a to 13d;

(13a)

(13a)

(13b)

(13b)

(13c)

(13c)

(13d)

(13d)

Where

A, B, Y, Z, R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R _{15 ,} R ₁₆ and R ₁₇ are the same as defined above;

R ₂₂ , R ₂₃ , R ₂₄ and R ₂₅ Are each independently a C ₁ -C ₃ alkyl group;

P ₁ Is an amine protecting group;

G ₁ Is nothing, hydrochloric acid, sulfuric acid, or trifluoroacetic acid.

The reaction may be carried out in the range of about −10 to 40 ° C. using an organic solvent such as dichloroethane or cyclized ether (eg, tetrahydrofuran (THF)) as a reaction solvent. The reaction mixture can be separated and purified using conventional methods such as chromatography.

Compound of Formula 12 may be preferably prepared by the following Scheme 1.

Scheme 1

Where

a is ClCO ₂ Et, Et ₃ N, THF; NaBH ₄ , MeOH;

b is TBSCl, imidazole, DMF;

c is Pd / C, H ₂ (benzyl ester) or LiOH-H ₂ O, MeOH-H ₂ O (methyl or ethyl ester);

d is EDC, HOBT, AH;

e is TBAF, THF;

f is Swern [O] or Dess Martin [O];

A and P ₁ Is the same as defined above;

P ₂ Is a benzyl group or a methyl or ethyl group.

Specifically, the carboxylic acid of Chemical Formula 14 is converted to anhydrous ester, and then reduced with sodium borohydride (NaBH ₄ ) in a methanol solvent to produce a primary alcohol. The primary alcohol thus produced is protected with a t-butyldimethylsilyl group and then removed with platinum complex and hydrogen in the case of benzyl ester or hydrolyzed with lithium hydroxide in the case of methyl or ethyl to obtain carboxylic acid. The desired amine group can be obtained by forming an amide through a coupling reaction using EDC and HOBT, removing the TBS group, and oxidizing with Swern or Dess-Martin to obtain an aldehyde of Chemical Formula 12. P ₁ , an amine protecting group, can be removed with TFA or HCl for Boc, H ₂ / Pd / C for Cbz or Et ₂ NH for Fmoc.

The amine A of Formula 12 may be obtained using commercially available amines or obtained using the methods described in the patents WO 04/064778, WO 03/004498, WO 03/082817 and the like.

In addition to the above-described method, a method for preparing the compound of Formula 12 from the compound of Formula 14 is known (see, eg, J. Med. Chem. 1999, 42 (18), 3557-3571; WO 04/069162, etc.). , These may be referred to.

In a second exemplary method of preparing the compound of Formula 1, the compound of Formula 13 is reacted with a compound of Formula 15 to remove the acid protecting group P ₃ , and the compound of Formula AH, wherein A Is the same) and the amine protecting group P ₁ is removed.

(15)

(15)

In the above formula, P ₁ Is the same as defined above; P ₃ Is a benzyl group or t-butyl group.

Specifically, the following reaction scheme 2 is mentioned.

Scheme 2

Where

a) is Na (OAc) ₃ BH, R ₂₁ NH ₂ G ₁ , and ClCH ₂ CH ₂ Cl;

b) is Boc ₂ O after Pd / C, H ₂ (benzyl ester) or TFA / CH ₂ Cl ₂ (t-Butyl ester, P ₁ = Boc);

c) is EDC, HOBT, AH;

d) is HCl / Dioxane;

A and B are as defined above;

P ₁ Is an amine protecting group such as Boc, Cbz, Fmoc;

P ₂ Is a benzyl group or t-butyl group;

G ₁ Is nothing, hydrochloric acid, sulfuric acid, or trifluoroacetic acid.

Methods of preparing compounds of Formula 16 are known (see, eg, J. Med. Chem. 1999, 42 (18), 3557-3571).

The reaction a) is a reaction solvent using a organic solvent such as dichloroethane or cyclized ether (eg, tetrahydrofuran (THF)) in the range of about -10 to 40 ℃, the primary amine ( Compound of formula 13) is preferably reacted with 0.7 to 1.5 equivalents. At this time, by proceeding to the cyclization reaction under the above conditions to synthesize a compound of formula 16, and the compound of formula 16 to obtain a carboxylic acid of formula 17 via the reaction b).

Where protector P ₂ In the case of benzyl, P ₂ is removed under H ₂ / Pd / C to synthesize carboxylic acid. P ₂ is t-butyl and P ₁ In the case of Boc, carboxylic acid is synthesized by simultaneously removing the protecting group with dichloromethane / TFA and then protecting the amine group with Boc again. Compound (18) is obtained using known reaction c) from carboxylic acid and amine AH obtained in the same manner as above.

In addition, P _{1 which is an} amine protecting group In the case of Boc, the compound of formula 1a is obtained by reaction d), and P ₁ Is Cbz, H ₂ / Pd / C or TMSI, P ₁ In the case of Fmoc, each of the amine protecting groups P ₁ is represented by Et ₂ NH. To remove the compound of formula 1a.

The amine AH in the reaction c) may be obtained by using methods described in the literature, such as WO 04/064778, WO 04/007468 or commercially available amines.

In the reaction c), the following amine group among the amines of AH can be synthesized, for example, by the same method as in Scheme 3 below.

Scheme 3

Where

a is LHMDS, CF ₃ CO ₂ Et, DME;

b is (1) R ₂₁ C = NH (NH ₂ ), EtOH or iPrOH, reflux,

(2) R ₂₁ C = NH (NH ₂ ) HCl, NaOEt, EtOH or iPrOH, reflux,

(3) R ₂₁ C = NH (NH ₂ ), cat. BF ₃ OEt ₂ , iPrOH, reflux,

(4) R ₂₁ C═NH (NH ₂ ), pyridine, reflux;

c is HCl / Dioxane or HCl / Ethyl Acetate;

R ₂₁ is hydrogen, an alkyl group or an aryl group.

That is, compound 20 may form an enolate from compound 19 with LHMDS, and then add ethyl trifluoroacetate to synthesize a desired compound (Ref. J. Fluorine Chem. 2003, 123 (2)). , 267-272). Compound 21 having a pyrimidine ring from compound 20 can be synthesized by various methods, including BF ₃ OEt ₂ as a catalyst (Synthesis 2000, 12, 1738-1748) and pyridine as a solvent. (Tetrahedron 1983, 39 (19), 3197-3199) are preferred for obtaining better yields. The desired amine (Compound 22) can be obtained using hydrochloric acid from Compound 21 obtained by the above method.

A third exemplary method for preparing the compound of Formula 1 includes reacting the compound of Formula 15 with a compound of Formula 23.

(23)

(23)

Wherein, G ₂ Is nothing or an acid, preferably hydrochloric acid, sulfuric acid, or trifluoroacetic acid; R ₂₆ Is hydrogen, a substituted or unsubstituted C ₁ -C ₄ alkyl group.

When the compound of Formula 15 and Formula 23 is reacted, the compound obtained by the same method as in Formula 13 of the second method is cyclized using phosphine (COCl ₂ ) to complete the B portion, and the subsequent reaction is Formula 1 may be synthesized in the same manner as in the method. Through the reaction of the compound of Formula 15 and Formula 23, a compound in which Z in Formula 10 is Z as a compound in which B is a substituent of Formula 10 in Formula 1 may be prepared.

Compounds used as starting materials in the present invention are known compounds or compounds which can be synthesized from known compounds by known synthesis methods or similar methods unless otherwise described.

The compound of Formula 1 may be separated or purified from the reaction product of the reaction by various methods such as recrystallization, iontophoresis, silica gel column chromatography or ion exchange resin chromatography.

As such, the compounds of the present invention, disclosures for their preparation, intermediates and the like may be synthesized by a variety of methods, which are construed as being within the scope of the present invention with respect to the preparation of compounds of formula 1 Should be.

The present invention also provides a pharmaceutical composition for inhibiting DPP-IV comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The compounds of the present invention can be formulated in a variety of pharmaceutical dosage forms as desired. In preparing the pharmaceutical composition according to the present invention, various pharmaceutically acceptable carriers, which may be selected according to the dosage form to prepare the active ingredient, specifically, the compound of formula (1), or a pharmaceutically acceptable salt thereof; Mix together. For example, the pharmaceutical composition according to the present invention may be formulated into an injectable preparation, an oral preparation, and the like as desired.

The compounds of the present invention can be formulated in a known manner using known pharmaceutical carriers and excipients and incorporated into unit dose forms or in multidose containers. The formulation form may be in the form of a solution, suspension or emulsion in oil or aqueous medium and may contain conventional dispersants, suspensions or stabilizers. In addition, for example, it may be in the form of a dry powder that is dissolved before use with sterile, pyrogen-free water. The compounds of the present invention may also be formulated into suppositories using conventional suppository bases such as cocoa butter or other glycerides. Solid dosage forms for oral administration may be capsules, tablets, pills, powders, and granules, and capsules and tablets are particularly useful. Tablets and pills are preferably prepared with enteric agents. Solid dosage forms can be prepared by mixing the compounds of the invention with one or more inert diluents, such as sucrose, lactose, starch, and the like, and carriers such as lubricants, disintegrants, binders, and the like, such as magnesium stearate.

If necessary, the compound according to the present invention or a pharmaceutical composition containing the same may be administered in combination with other drugs, for example, other antidiabetic agents.

When formulated in unit dose form, the compound of formula 1 as the active ingredient is preferably contained in unit doses of about 0.1 to 1,500 mg. The dosage of the compound of formula 1 depends on the doctor's prescription depending on factors such as the patient's weight, age and the particular nature and severity of the disease. However, the dosage required for adult treatment typically ranges from about 1 to 500 mg per day, depending on the frequency and intensity of administration. A total dosage of about 5 to 300 mg per day, usually separated by a single dose for intramuscular or intravenous administration to an adult, will be sufficient, but for some patients a higher daily dosage may be desirable.

The present invention provides a method of using the compound of formula 1 in the manufacture of a medicament for the treatment or prevention of diseases caused by DPP-IV.

Representative examples of diseases caused by DPP-IV include, but are not limited to, diabetes and obesity. Among diabetes, it is particularly useful for the treatment and prevention of type II diabetes.

Hereinafter, the present invention will be described in more detail with reference to Preparation Examples and Examples, but the scope of the present invention is not limited thereto.

Production Example  1: 3- Aminomethyl -4,4,4- Trifluoro - Butyric acid  Synthesis of Ethyl Ester Hydrochloride

(One) 4,4,4- Trifluoro -3- Nitromethyl - Butyric acid  Synthesis of Ethyl Ester

4,4,4-trifluoro-2-butenonic acid ethyl ester (1 g, 5.94 mM) and 1,1,3,3-tetramethyl guanidine (0.15 ml, 1.19 mmol) were mixed, followed by 0 ° C. After cooling to 3 hours at room temperature, 100 ml of ethylacetoacetate was added. The reaction was washed with water and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 1.1 g (4.80 mM) of the title compound in 81% yield.

NMR: ¹ H-NMR (CDCl ₃ ) δ 5.21 to 4.59 (2H, m), 4.22 (2H, q, J = 8 Hz), 3.67 to 3.64 (1H, m), 2.82 to 2.72 (1H, m), 2.63 ~ 2.57 (1H, m), 1.28 (3H, t, J = 8 Hz)

Mass (EI) 176 (M ⁺ +1)

(2) N-hydroxy-3- (t- Butoxycarbonylamino - methyl ) -4,4,4- Trifluoro - Butyric acid Synthesis of Ethyl Ester

4,4,4-trifluoro-3-nitromethyl-butyric acid ethyl ester (1.1 g, 4.80 mmol) obtained in step (1) was dissolved in 20 ml of methanol, followed by di-t-butyl dicarbonate (1.85). g, 8.47 mmol) was added and reacted with pressurization for 15 hours with 180 mg of 10% palladium / carbon. After filtration through celite and distillation under reduced pressure, 1.5 g (4.80 mmol) of the title compound were obtained by column chromatography in 100% yield.

NMR: ¹ H-NMR (CDCl ₃ ) δ 6.48 (1H, s), 4.20 (2H, q, J = 8 Hz), 3.89 to 3.83 (1H, m), 3.66 to 3.62 (1H, m), 3.24 to 3.17 (1H, m), 2.76-2.68 (1H, m), 2.53 (1H, dd, J = 8 Hz, 16 Hz), 1.48 (9H, s), 1.25 (3H, t, J = 8 Hz)

Mass (EI) 262 (M ⁺ +1)

(3) 3- (t- Butoxycarbonylamino - methyl ) -4,4,4- Trifluoro - Butyric acid  Synthesis of Ethyl Ester

N-hydroxy-3- (t-butoxycarbonylamino-methyl) -4,4,4-trifluoro-butyric acid ethyl ester (760 mg, 2.41 mmol) obtained in the above step (2) was added to methanol 80. After dissolving in 40 ml of water and sodium acetate (2.4 g, 28.9 mmol), 20% aqueous titanium trichloride solution (4 ml, 4.81 mmol) was slowly added dropwise at room temperature. After 20 minutes, ethylacetoacetate (300 ml) was added, washed with water, and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure and then column chromatography gave 550 mg (2.24 mM) of the title compound in 92% yield.

NMR: ¹ H-NMR (CDCl ₃ ) δ 4.70 (1H, s), 4.18 (2H, q, J = 6.8 Hz), 3.64 to 3.53 (1H, m), 3.35 to 3.34 (1H, m), 3.05 to 2.90 (1H, m), 2.60 (1H, dd, J = 5.2 Hz, 16.4 Hz), 2.48 (1H, dd, J = 8 Hz, 16.4 Hz), 1.43 (9H, s), 1.27 (3H, t, J = 6.8 Hz)

Mass (EI) 246 (M ⁺ +1)

(4) 3- Aminomethyl -4,4,4- Trifluoro - Butyric acid  Synthesis of Ethyl Ester Hydrochloride

3- (t-butoxycarbonylamino-methyl) -4,4,4-trifluoro-butyric acid ethyl ester (170 mg, 0.69 mM) obtained in the step (3) was ethyl acetate saturated with hydrochloric acid gas. It was dissolved in 6 ml and stirred at room temperature for 3 hours. After distillation of the solvent under reduced pressure, 110 mg (0.69 mM) of the title compound were obtained by column chromatography in 86% yield.

NMR: ¹ H-NMR (CDCl ₃ ) δ 8.50 (2H, brs), 4.18 (2H, q, J = 4 Hz), 3.50-3.20 (3H, m), 2.97-2.64 (2H, m), 1.24 (3H , t, J = 4 Hz)

Mass (EI) 182 (M ⁺ +1)

Production Example  2: 4-amino-3- methyl - Butyric acid methyl  Synthesis of Ester Hydrochloride

(One) 3- methyl 4-nitro- Butyric acid methyl  Synthesis of Ester

Trans-2-butenonic acid methyl ester (3 g, 29.9 mM), tetramethylguanidine (0.69 g, 5.99 mM) and nitromethane (9.14 g, 149 mM) were mixed, and then stirred at room temperature for 24 hours, followed by ethyl Acetate (100 ml) was added, washed with water and the organic layer was dried over magnesium sulfate. After distillation of the solvent under reduced pressure, 5.7 g (23.6 mM) of the title compound were obtained in 100% yield.

NMR: 1 H-NMR (CDCl ₃ ) δ 4.48 (1H, dd, J = 4 Hz, 12 Hz), 4.35 (1H, dd, J = 4 Hz, 12 Hz), 3.71 (3H, s), 2.84 to 2.74 (1H, m ), 2.47 (1H, dd, J = 4 Hz, 16 Hz), 2.37 (1H, dd, J = 8 Hz, 16 Hz), 1.11 (3H, d, J = 8 Hz)

Mass (EI) 162 (M ⁺ +1)

(2) N-t- Butyloxycarbonylhydroxy -4-t- Butoxycarbonylamino -3,3-dimethyl- Butyric acid  Synthesis of Methyl Ester

3-methyl-4-nitro-butyric acid methyl ester (4 g, 24.8 mM) obtained in the above step (1) was dissolved in 50 ml of methanol, followed by di-t-butyldicarbonate (10.4 g, 47.6 mM). After addition, the reaction was performed by pressing for 10 hours at 50 psi with 500 mg of 10% palladium / carbon. The reaction was filtered through celite, distilled under reduced pressure, and then purified by column chromatography to give 3.6 g (10.3 mM) of the title compound and N-hydroxy-4-t-butoxycarbonylamino-3,3-dimethyl-butyric acid. 1.1 g (4.45 mM) of methyl ester were obtained in 62% yield.

Mass (EI) 348 (M ⁺ +1)

(3) N-hydroxy-4-t- Butoxycarbonylamino -3,3-dimethyl- Butyric acid Methyl ester  synthesis

Nt-butyloxycarbonylhydroxy-4-t-butoxycarbonylamino-3,3-dimethyl-butyric acid methyl ester (600 mg, 1.72 mM) obtained in step (2) was dissolved in 80 ml of methanol. 250 mg sodium bicarbonate was added dropwise and stirred at 80 ° C. for 9 hours. 200 ml of ethyl acetate was added to the reaction, washed with water, and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then column chromatography gave 332 mg (1.34 mM) of the title compound in 77% yield.

NMR: 1 H-NMR (CDCl ₃ ) δ 7.27 (1H, brs), 3.49 (3H, s), 3.46 (1H, dd, J = 4 Hz, 12 Hz), 3.33 (1H, dd, J = 5.6 Hz, 14.4 Hz ), 2.51 to 2.42 (1H, m), 2.39 (1H, dd, J = 4 Hz, 16 Hz), 2.22 (1H, dd, J = 4 Hz, 16 Hz), 1.48 (9H, s), 0.98 (3H, d, J = 8Hz)

Mass (EI) 248 (M ⁺ +1)

(4) 4-t- Butoxycarbonylamino -3- methyl - Butyric acid Methyl ester  synthesis

N-hydroxy-4-t-butoxycarbonylamino-3,3-dimethyl-butyric acid methyl ester (330 mg, 1.33 mM) obtained in step (3) was prepared. 213 mg (0.92 mM) of the title compound were obtained in 47% yield.

NMR: 1 H-NMR (CDCl ₃ ) δ 4.65 (1H, brs), 3.68 (3H, s), 3.10-3.00 (2H, m), 2.38-2.33 (1H, m), 2.20-2.05 (2H, m) , 1.44 (9H, s), 0.96 (3H, d, J = 8 Hz)

Mass (EI) 232 (M ⁺ +1)

(5) 4-amino-3- methyl - Butyric acid methyl  Synthesis of Ester Hydrochloride

The 4-t-butoxycarbonylamino-3-methyl-butyric acid methyl ester (100 mg, 0.43 mM) obtained in the step (4) was obtained by using the experimental method of Preparation Example 1 (4) 62 mg ( 0.36 mM) was obtained in 83% yield.

NMR: 1 H-NMR (CDCl ₃ ) δ 8.26 (2H, brs), 3.68 (3H, s), 3.10-2.99 (2H, m), 2.77-2.35 (3H, m), 1.13 (3H, d, J = 8 Hz)

Mass (EI) 168 (M ⁺ +1)

Production Example  3: 4-amino-2-fluoro- Butyric acid methyl  Synthesis of Ester Hydrochloride

(One) 2-oxo- Pyrrolidine Synthesis of -1-carboxylic acid t-butyl ester

2-pyrrolidine (1 g, 11.7 mM) was dissolved in 15 ml of dichloromethane, followed by 2.5 ml (17.8 mM) of triethylamine, dimethylaminopyridine (107 mg, 0.87 mM) and di-t-butyl dicarbonate (2.7 g, 12.3 mM). After stirring for 8 hours at room temperature, 100 ml of ethylacetoacetate was added, washed with water, and the organic layer was dried over magnesium sulfate. After distillation of the solvent under reduced pressure, 1.2 g (6.47 mM) of the title compound was obtained by 55% yield using column chromatography.

NMR: 1 H-NMR (CDCl ₃ ) δ 3.76-3.73 (2H, m), 2.53-2.49 (2H, m), 2.04-1.88 (2H, m), 1.53 (9H, s)

Mass (EI) 186 (M ⁺ +1)

(2) 3- Fluoro 2-oxo- Pyrrolidine Synthesis of -1-carboxylic acid t-butyl ester

The 2-oxo-pyrrolidine-1-carboxylic acid t-butyl ester (300 mg, 1.61 mM) obtained in the above step (1) was dissolved in tetrahydrofuran and the temperature was lowered to -78 ° C. 1.7 ml (1.7 mM) of 1.0 M lithium bis (trimethylsilyl) amide tetrahydrofuran solution was slowly added dropwise and stirred for 1 hour. N-fluorobenzenesulfonimide (561 mg, 1.78 mM) was added and the temperature was raised to -30 ° C. for 2 hours, 100 ml of ethyl acetate was added thereto, washed with an aqueous ammonium chloride solution and the organic layer was dried over magnesium sulfate. It was. After distillation of the solvent under reduced pressure, 60 mg (0.29 mM) of the title compound was obtained in 18% yield by column chromatography.

NMR: 1 H-NMR (CDCl ₃ ) δ 5.16 to 5.12 (0.5H, m), 5.01 to 4.94 (0.5H, m), 3.91 to 3.85 (1H, m), 3.64 to 3.57 (1H, m), 2.50 to 2.45 (1H, m), 2.25-2.13 (1H, m), 1.54 (9H, s)

Mass (EI) 204 (M ⁺ +1)

(3) 4-t- Butoxycarbonylamino -2- Fluoro - Butyric acid methyl  Synthesis of Ester

3-fluoro-2-oxo-pyrrolidine-1-carboxylic acid t-butyl ester (60 mg, 0.29 mM) obtained in the above step (2) was dissolved in 3 ml of methanol, followed by sodium methoxide (32 mg, 0.59 mM). ) Was added at 0 ° C. After 1 hour, 10 ml of ethyl acetate was added, washed with an aqueous ammonium chloride solution, and the organic layer was dried over magnesium sulfate. After distillation of the solvent under reduced pressure, 49 mg (0.29 mM) of the title compound was obtained in 18% yield by column chromatography.

Mass (EI) 236 (M ⁺ +1)

(4) 4-amino-2- Fluoro - Butyric acid methyl  Synthesis of Ester Hydrochloride

17 mg of the title compound from the 4-t-butoxycarbonylamino-2-fluoro-butyric acid methyl ester (50 mg, 0.21 mM) obtained in the step (3) using the experimental method of Preparation Example 1 (4). (0.099 mM) was obtained in 47% yield.

NMR: 1H-NMR (CD ₃ OD) δ 5.24 to 5.20 (0.5H, m), 5.15 to 4.95 (0.5H, m), 3.81 (3H, s), 3.21 to 3.08 (2H, m), 2.40 to 2.10 (2H, m)

Mass (EI) 172 (M ⁺ +1)

Production Example  4: 5-amino-2- Fluoro - Pentanoic acid methyl  Synthesis of Ester Hydrochloride

(One) Synthesis of 2-oxo-piperidine-1-carboxylic acid t-butyl ester

1.17 g (8.88 mM) of the title compound were obtained in 88% yield using the experimental method of Preparation Example 3 (1) from 2-piperidine (1 g, 10.08 mM).

NMR: 1 H-NMR (CDCl ₃ ) δ 3.67 to 3.64 (2H, m), 2.52 to 2.49 (2H, m), 1.86 to 1.78 (4H, m), 1.53 (9H, s)

Mass (EI) 200 (M ⁺ +1)

(2) 3- Fluoro Synthesis of 2-oxo-piperidine-1-carboxylic acid t-butyl ester

160 mg (0.73 mM) of the title compound using the experimental method of Preparation Example 3 (2) from 2-oxo-piperidine-1-carboxylic acid t-butyl ester (300 mg, 1.5 mM) obtained in the above step (1). Was obtained in 48% yield.

NMR: 1 H-NMR (CDCl ₃ ) δ 5.03 to 4.75 (1H, m), 3.75 to 3.55 (2H, m), 2.35 to 2.22 (1H, m), 2.05 to 1.78 (3H, m), 1.54 (9H, s)

Mass (EI) 218 (M ⁺ +1)

(3) 5-t- Butoxycarbonylamino -2- Fluoro - Pentanoic acid methyl  Synthesis of Ester

The title compound 56 from the 3-fluoro-2-oxo-piperidine-1-carboxylic acid t-butyl ester (160 mg, 0.73 mM) obtained in the step (2) using the experimental method of Preparation Example 3 (3). mg (0.22 mM) was obtained in 30% yield.

NMR: 1 H-NMR (CDCl ₃ ) δ 5.02 to 4.87 (1H, m), 4.63 (1H, brs), 3.80 (3H, s), 3.25 to 3.05 (2H, m), 1.99 to 1.88 (2H, m) , 1.72-1.64 (2H, m), 1.44 (9H, s)

Mass (EI) 250 (M ⁺ +1)

(4) 5-amino-2- Fluoro - Pentanoic acid methyl  Synthesis of Ester Hydrochloride

Title compound 40 using the experimental method of Preparation Example 1 (4) from 5-t-butoxycarbonylamino-2-fluoro-pentanoic acid methyl ester (56 mg, 0.224 mM) obtained in the step (3). mg (0.21 mM) was obtained in 95% yield.

NMR: 1H-NMR (CDCl ₃ ) δ 5.15-4.95 (1H, m), 3.81 (3H, s), 3.00-2.90 (2H, m), 2.10-1.73 (4H, m)

Mass (EI) 186 (M ⁺ +1)

Production Example  5: 4-amino-2- methyl - Butanoic acid methyl  Synthesis of Ester Hydrochloride

(One) 3- methyl 2-oxo- Pyrrolidine Synthesis of -1-carboxylic acid t-butyl ester

2-oxo-pyrrolidine-1-carboxylic acid t-butyl ester (300 mg, 1.61 mM) was dissolved in tetrahydrofuran and the temperature was lowered to -78 ° C. Then, 1.7 ml (1.7 mM) of 1.0 M lithium bis (trimethylsilyl) amide tetrahydrofuran solution was slowly added dropwise and stirred for 1 hour. Iodomethane (0.19 ml, 3.05 mM) was added and slowly warmed to -30 ° C. for 2 hours, 50 ml of ethyl acetate was added, washed with an aqueous ammonium chloride solution, and the organic layer was dried over magnesium sulfate. After distillation of the solvent under reduced pressure, 130 mg (0.65 mM) of the title compound were obtained in 40% yield by column chromatography.

NMR: 1H-NMR (CDCl ₃ ) δ 3.79 to 3.74 (1H, m), 3.61 to 3.54 (1H, m), 2.59 to 2.53 (1H, m), 2.25 to 2.17 (1H, m), 1.67 to 1.59 ( 1H, m), 1.53 (9H, s), 1.20 (3H, d, J = 12 Hz)

Mass (EI) 200 (M ⁺ +1)

(2) 4-t- Butoxycarbonylamino -2- methyl - Butanoic acid methyl  Synthesis of Ester

120 mg of the title compound from the 3-methyl-2-oxo-pyrrolidine-1-carboxylic acid t-butyl ester (130 mg, 0.65 mM) obtained in the step (1) using the experimental method of Preparation Example 3 (3). (0.51 mM) was obtained in 78% yield.

NMR: 1H-NMR (CDCl ₃ ) δ 4.58 (1H, brs), 3.68 (3H, s), 3.17-3.14 (2H, m), 2.55-2.47 (1H, m), 1.89-1.80 (1H, m) , 1.67-1.60 (1H, m), 1.44 (9H, s), 1.19 (3H, d, J = 4 Hz)

Mass (EI) 232 (M ⁺ +1)

(3) 4-amino-2- methyl - Butanoic acid methyl  Synthesis of Ester Hydrochloride

80 mg of the title compound using the experimental method of Preparation Example 1 (4) from 4-t-butoxycarbonylamino-2-methyl-butyric acid methyl ester (120 mg, 0.51 mM) obtained in the step (2). 0.47 mM) was obtained in 92% yield.

NMR: 1 H-NMR (CD ₃ OD) δ 3.70 (3H, s), 3.05 to 2.90 (2H, m), 2.65 to 2.55 (1H, m), 2.05 to 1.70 (2H, m), 1.23 (3H, d , J = 6Hz)

Mass (EI) 168 (M ⁺ +1)

Production Example  6: 4-amino-3- methyl -2- Butene acid methyl  Synthesis of Ester Hydrochloride

(One) (2-hydroxy-propyl)- Carbamic acid  Synthesis of t-butyl ester

Dissolve 1-amino-propan-2-ol (1 g, 13.3 mM) in 40 ml of methanol and 10 ml of water, add di-t-butyl dicarbonate (3.7 g, 16.9 mM) and stir at room temperature for 3 hours. It was. 200 ml of ethyl acetate was added to the reaction, washed with water, and the organic layer was dried over magnesium sulfate. After distillation of the solvent under reduced pressure, 2.24 g (12.8 mM) of the title compound were obtained by using column chromatography in 96% yield.

NMR: 1 H-NMR (CDCl ₃ ) δ 4.91 (1 H, brs), 3.95 to 3.85 (1 H, m), 3.30 to 3.22 (1 H, m), 3.05 to 2.95 (1 H, m), 1.43 (9 H, s) , 1.16 (3H, d, J = 4 Hz)

Mass (EI) 176 (M ⁺ +1)

(2) (2-oxo-propyl)- Carbamic acid  Synthesis of t-butyl ester

(2-hydroxy-propyl) -carbamic acid t-butyl ester (2.24 g, 12.7 mM) obtained in the above step (1) was dissolved in 30 ml of dichloromethane, and 3.6 ml (25.7 mM) of triethylamine was added dropwise. It was. A solution of sulfa trioxide pyridine (50%, 6.05 g, 19 mM) in 15 ml of dimethylsulfoxide was added to the reaction mixture, after 6 hours, 200 ml of ethyl acetate was added, washed with water, and the organic layer was dried over magnesium sulfate. . The solvent was distilled off under reduced pressure and then column chromatography gave 1.15 g (6.64 mM) of the title compound in 52% yield.

NMR: 1 H-NMR (CDCl ₃ ) δ 5.20 (1H, brs), 4.05-4.00 (2H, m), 2.17 (3H, s), 1.43 (9H, s)

Mass (EI) 174 (M ⁺ +1)

(3) Sheath -4-t- Butoxycarbonylamino -3- methyl -2- Butene acid Methyl ester  synthesis

(2-oxo-propyl) -carbamic acid t-butyl ester (500 mg, 2.88 mM) obtained in step (2) was dissolved in 8 ml of benzene, followed by methyl (triphenylphosphoranilidene) acetate (1.45 g, 4.33 mM) and benzoic acid (35 mg, 0.28 mM) were added and then heated at 80 ° C. for 3 hours. The solvent was distilled off under reduced pressure, and column chromatography gave 301 mg (1.31 mM, 45% yield) of the trans compound and 54 mg (6.64 mM, 23% yield) of the title compound.

NMR: 1 H-NMR (CDCl ₃ ) δ 5.77 (1H, s), 5.17 (1H, brs), 4.16 (2H, d, J = 6.4 Hz), 3.69 (3H, s), 2.05 (3H, s), 1.44 (9 H, s)

Mass (EI) 230 (M ⁺ +1)

(4) 4-amino-3- methyl -2- Butene acid methyl  Synthesis of Ester Hydrochloride

From cis-4-t-butoxycarbonylamino-3-methyl-2-butenioic acid methyl ester (54 mg, 0.235 mM) obtained in the step (3), using the experimental method of Preparation Example 1 (4) 30 mg (0.23 mM) of the title compound were obtained in 97% yield.

NMR: 1 H-NMR (CD ₃ OD) δ 6.05 (1H, s), 4.00 (2H, s), 3.72 (3H, s), 3.29-3.28 (2H, m), 2.05 (3H, s)

Mass (EI) 130 (M ⁺ +1)

Production Example  7: (R) -5-amino-4- methyl - Pentanoic acid methyl  Synthesis of Ester Hydrochloride

(One) (S) -3- Methanesulfonyloxy -2- methyl - Propionic acid methyl  Synthesis of Ester

(S) -3-hydroxy-2-methyl-propionic acid methyl ester (3 g, 25.3 mM) was dissolved in 50 ml of dichloromethane, and 5.3 ml (37.9 mM) of triethylamine was added dropwise. Methanesulfonyl chloride (2.16 ml, 27.9 mM) was then added at 0 ° C. After 1 hour, 200 ml of ethylacetoacetate was added, washed with water, and the organic layer was dried over magnesium sulfate. After distillation of the solvent under reduced pressure, 4.97 g (25.3 mM) of the title compound was obtained by using column chromatography in 100% yield.

Mass (EI) 197 (M ⁺ +1)

(2) (S) -3- A map -2- methyl - Propionic acid methyl  Synthesis of Ester

(S) -3-methanesulfonyloxy-2-methyl-propionic acid methyl ester (4.97 g, 25.3 mM) obtained in step (2) was dissolved in 40 ml of dimethylformamide, followed by sodium azide (5 g, 76.8 mM) is added and stirred at 60 ° C. for 24 hours. After adding 200 ml of ethyl acetoacetate and washing with water, the organic layer was dried over magnesium sulfate. After distilling off the solvent under reduced pressure, 3.5 g (24.4 mM) of the title compound was obtained by using column chromatography in 96% yield.

NMR: 1 H-NMR (CDCl ₃ ) δ 3.71 (3H, s), 3.54 to 3.52 (1H, m), 3.40 to 3.30 (1H, m), 2.80 to 2.65 (1H, m), 1.20 (3H, d, J = 7.2 Hz)

Mass (EI) 144 (M ⁺ +1)

(3) (S) -3-t- Butoxycarbonylamino -2- methyl - Propionic acid methyl  Synthesis of Ester

(S) -3-azido-2-methyl-propionic acid methyl ester (3.9 g, 26.8 mM) obtained in step (2) was dissolved in 50 ml of methanol, followed by di-t-butyl dicarbonate (8.8). g, 40.3 mM) was added and reacted with 400 mg of 10% palladium / carbon for 9 hours under hydrogen. After filtration through celite and distillation under reduced pressure, 2.6 g (11.9 mM) of the title compound were obtained by column chromatography in 44% yield.

NMR: 1 H-NMR (CDCl ₃ ) δ 4.92 (1H, brs), 3.70 (3H, s), 3.31-3.20 (2H, m), 2.70-2.55 (1H, m), 1.43 (9H, s), 1.15 (3H, d, J = 12 Hz)

Mass (EI) 218 (M ⁺ +1)

(4) (S)-(3-hydroxy-2- methyl -profile)- Carbamic acid  t- Butyl ester  synthesis

(S) -3-t-butoxycarbonylamino-2-methyl-propionic acid methyl ester (500 mg, 2.30 mM) obtained in step (3) was dissolved in 30 ml of tetrahydrofuran, and then lithium aluminum hydride. (262 mg, 6.9 mM) is added slowly at 0 ° C. After raising the temperature to room temperature, the reaction was carried out for 4 hours. After the temperature of the reaction was lowered to 0 ° C., 0.26 ml of water, 0.26 ml of 15% sodium hydroxide solution, and 0.78 ml of water were slowly added. After filtration in the presence of celite, the solvent was removed and the residue was purified by column chromatography to give 430 mg (2.27 mM) of the title compound in 98% yield.

NMR: 1 H-NMR (CDCl ₃ ) δ 4.78 (1H, brs), 3.55 to 3.50 (1H, m), 3.33 to 3.20 (2H, m), 3.05 to 2.98 (1H, m), 1.75 to 1.65 (1H, m), 1.46 (9H, s), 0.87 (3H, d, J = 12 Hz)

Mass (EI) 190 (M ⁺ +1)

(5) (S)-(2- methyl -3-oxo-propyl)- Carbamic acid  t- Butyl ester  synthesis

Experimental method of Preparation Example 6 (2) from (S)-(3-hydroxy-2-methyl-propyl) -carbamic acid t-butyl ester (430 mg, 2.27 mM) obtained in step (4). 423 mg (2.26 mM) of the title compound were obtained in 99% yield.

Mass (EI) 188 (M ⁺ +1)

(6) (R) -5-t- Butoxycarbonylamino -4- methyl -2- Pentenoic acid Methyl ester  synthesis

From (S)-(2-methyl-3-oxo-propyl) -carbamic acid t-butyl ester (423 mg, 2.26 mM) obtained in the step (5), using the experimental method of Preparation Example 6 (3). 380 mg (2.26 mM) of the title compound were obtained in 99% yield.

NMR: 1 H-NMR (CDCl ₃ ) δ 6.84 (1H, dd, J = 15 Hz, 10 Hz), 5.84 (1H, d, J = 15 Hz), 4.55 (1H, brs), 3.72 (3H, s), 3.25- 3.15 (1H, m), 3.06-3.00 (1H, m), 2.54-2.47 (1H, m), 1.42 (9H, s), 1.03 (3H, d, J = 15 Hz)

Mass (EI) 244 (M ⁺ +1)

(7) (R) -5-t- Butoxycarbonylamino -4- methyl - Pentanoic acid Methyl ester  synthesis

(R) -5-t-butoxycarbonylamino-4-methyl-2-pentenoic acid methyl ester (370 mg, 2.26 mM) obtained in step (6) was dissolved in 50 ml of methanol and then sold 20%. It was reacted with hydrogen 40 mg of sodium hydroxide for 9 hours under hydrogen. It was filtered through celite and distilled under reduced pressure to give 310 mg (1.26 mM) of the title compound in 55% yield using column chromatography.

NMR: 1H-NMR (CDCl ₃ ) δ 4.87 (1H, brs), 3.67 (3H, s), 3.05-2.96 (2H, m), 2.39-2.27 (2H, m), 1.75-1.40 (3H, m) , 1.44 (9H, s), 0.87 (3H, d, J = 12 Hz)

Mass (EI) 246 (M ⁺ +1)

(8) (R) -5-amino-4- methyl - Pentanoic acid methyl  Synthesis of Ester Hydrochloride

From (R) -5-t-butoxycarbonylamino-4-methyl-pentanoic acid methyl ester (310 mg, 1.26 mM) obtained in the step (7), using the experimental method of Preparation Example 1 (4) 220 mg (1.21 mM) of the title compound were obtained in 96% yield.

NMR: 1H-NMR (CD ₃ OD) δ 3.87 (3H, s), 2.96-2.91 (1H, m), 2.81-2.76 (1H, m), 2.47-2.40 (2H, m), 1.88-1.76 (2H , m), 1.56 to 1.50 (1H, m), 1.04 (3H, d, J = 6.4 Hz)

Mass (EI) 182 (M ⁺ +1)

Production Example  8: 5-amino-3- methyl - Pentanoic acid methyl  Synthesis of Ester Hydrochloride

(One) 4- methyl Piperidine-1- Cabolic acid  t- Butyl ester  synthesis

3.5 mg (17.5 mM) of the title compound were obtained in 87% yield using the experimental method of Preparation Example 6 (1) from 4-methylpiperidine (2 g, 20.1 mM).

Mass (EI) 200 (M ⁺ +1)

(2) 4- methyl -2-oxo-piperidine-1- Cabolic acid  t- Butyl ester  synthesis

4-Methyl-piperidine-1-carbosilic acid t-butyl ester (1 g, 5.02 mM) obtained in the step (1) was dissolved in 70 ml ethyl acetate. A solution of sodium periodate (5.4 g, 25.2 mM) and ruthenium dioxide (247 mg, 1.85 mM) in 40 ml of water was added dropwise to the reaction solution. After 3 hours, 5% sodium thiosulfate was added and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, distilled under reduced pressure, and then subjected to column chromatography to give 750 mg (3.52 mM) of the title compound in 70% yield.

NMR: ¹ H-NMR (CDCl ₃ ) δ 4.11 to 3.77 (1H, m), 3.53 to 3.49 (1H, m), 2.62 to 2.56 (1H, m), 2.15 to 1.90 (3H, m), 1.49 (9H , s), 1.48-1.26 (1H, m), 1.02 (3H, d J = 4 Hz)

Mass (EI) 214 (M ⁺ +1)

(3) 5-t- Butoxycarbonylamino -3- methyl - Pentanoic acid methyl  Synthesis of Ester

The title compound using the experimental method of Preparation Example 3 (3) from 4-methyl-2-oxo-piperidine-1-carbosilic acid t-butylester (368 mg, 1.72 mM) obtained in the above step (2). 410 mg (1.67 mM) were obtained in 97% yield.

¹ H NMR (CDCl ₃ ) δ 4.5-4.6 (1H, br s), 3.65 (3H, s), 3.0-3.2 (2H, m), 2.3 (1H, m), 2.15 (1H, m), 2.0 ( 1H, m), 1.4-1.5 (2H, m), 1.45 (9H, s)

Mass (m / e) 268 (M + Na)

(4) 5-amino-3- methyl - Pentanoic acid methyl  Synthesis of Ester Hydrochloride

From 410 mg (1.67 mM) of 5-t-butoxycarbonylamino-3-methyl-pentanoic acid methyl ester obtained in the step (3), using the experimental method of Preparation Example 1 (4), 226 mg ( 1.24 mM) was obtained in 74% yield.

¹ H NMR (CD ₃ OD) δ 3.65 (3H, s), 2.9-3.0 (2H, m), 2.34 (1H, dd, J = 15, 7 Hz), 2.27 (1H, dd, J = 15, 7 Hz), 2.0 (1H, m), 1.7 (1H, m), 1.54 (1H, m), 0.98 (3H, d, J = 7 Hz)

Mass (m / e) 146 (M + 1)

Production Example  9: 4- Aminomethyl -5,5,5- Trifluoro - Pentanoic acid methyl  Synthesis of Ester Hydrochloride

(One) 5- Trifluoromethyl Synthesis of -piperidin-2-one

5-trifluoromethyl-2-pyridinol (1 g, 6.13 mM) was dissolved in 20 ml of acetic acid and reacted under pressure at 50 psi for 9 hours with 300 mg of platinum oxide. Then filtered through celite and distilled under reduced pressure to give 920 mg (5.50 mM) of the title compound in 89% yield using column chromatography.

NMR: ¹ H-NMR (CDCl ₃ ) δ 3.56 ~ 3.51 (1H, m), 3.42 ~ 3.36 (1H, m), 2.59 ~ 2.53 (2H, m), 2.45 ~ 2.41 (1H, m), 2.19 ~ 2.13 (1H, m), 1.95-1.87 (1H, m)

Mass (EI) 168 (M ⁺ +1)

(2) 2-oxo-5- Trifluoromethyl Piperidine-1- Carboxylic acid  t- Butyl ester  synthesis

5-trifluoromethyl-piperidin-2-one (1.3 g, 7.7 mM) obtained in step (1) was dissolved in 10 ml of acetonitrile and then 2.0 ml (14.3 mM) of triethylamine and dimethylaminopyridine ( 48 mg, 0.39 mM) and di-t-butyl dicarbonate (1.8 g, 8.2 mM) were added. After stirring at 80 ° C. for 4 hours, 100 ml of ethyl acetate was added, washed with water, and the organic layer was dried over magnesium sulfate. After distillation of the solvent under reduced pressure, 669 mg (2.5 mM) of the title compound were obtained by using column chromatography in 32% yield.

NMR: ¹ H-NMR (CDCl ₃ ) δ 4.09 to 3.97 (1H, m), 3.77 to 3.71 (1H, m), 2.70 to 2.47 (3H, m), 2.15 to 2.10 (1H, m), 1.97 to 1.89 (1H, m), 1,50 (9H, s)

Mass (EI) 268 (M ⁺ +1)

(3) 4- (t- Butoxycarbonylamino - methyl ) -5,5,5- Trifluoro - Pentanoic acid Methyls Synthesis of Ter

From the 2-oxo-5-trifluoromethyl-piperidine-1-carboxylic acid t-butyl ester (669 mg, 2.5 mM) obtained in the step (2), using the experimental method of Preparation Example 3 (3). 500 mg (1.67 mM) of the title compound were obtained in 66% yield.

NMR: ¹ H-NMR (CDCl ₃ ) δ 4.76 (1H, s), 3.68 (3H, s), 3.45 to 3.30 (2H, m), 2.55 to 2.48 (2H, m), 2.40 to 2.32 (1H, m) ), 2.00-1.95 (1H, m), 1.90-1.80 (1H, m), 1,43 (9H, s)

Mass (EI) 300 (M ⁺ +1)

(4) 4- Aminomethyl -5,5,5- Trifluoro - Pentanoic acid methyl  Ester of hydrochloride synthesis

Preparation Example 1 (4) from 500 mg (1.67 mM) of 4- (t-butoxycarbonylamino-methyl) -5,5,5-trifluoro-pentanoic acid methyl ester obtained in step (3). Using the experimental method, 335 mg (1.42 mM) of the title compound were obtained in 85% yield.

NMR: ¹ H-NMR (CDCl ₃ ) δ 8.48 (2H, s), 3.69 (3H, s), 3.50-3.40 (1H, m), 3.30-3.15 (1H, m), 2.99-2.89 (1H, m ), 2.65-2.52 (2H, m), 2.11-1.91 (2H, m)

Mass (EI) 236 (M ⁺ +1)

Production Example  10: (2-amino-1- methyl - Ethoxy )- Acetic acid  Synthesis of Ethyl Ester Hydrochloride

(One) (2-t- Butoxycarbonylamino -One- methyl - Ethoxy )- Acetic acid  Synthesis of Ethyl Ester

After dissolving (2-hydroxy-propyl) -carbamic acid t-butyl ester (500 mg, 2.85 mM) in 10 ml of dichloroethane, 0.44 ml (4.24 mM) of ethyl diazoacetate was added thereto. Rhodium acetate (38 mg, 0.085 mM) was added dropwise to the reaction solution, followed by heating at 80 ° C. for 2 hours. After distillation of the solvent under reduced pressure, 381 mg (1.45 mM) of the title compound was obtained by using column chromatography in 50% yield.

NMR: ¹ H-NMR (CDCl ₃ ) δ 5.39 (1H, s), 4.23 (2H, q, J = 8 Hz), 4.09 (1H, d, J = 16 Hz), 4.00 (1H, d, J = 16 Hz) , 3.60-3.35 (1H, m), 3.35-3.15 (1H, m), 3.10-3.04 (1H, m), 1.46 (9H, s), 1.31 (3H, t, J = 4 Hz), 1.16 (3H, d, J = 4 Hz)

Mass (EI) 262 (M ⁺ +1)

(2) (2-amino-1- methyl - Ethoxy )- Acetic acid  Synthesis of Ethyl Ester Hydrochloride

From (2-t-butoxycarbonylamino-1-methyl-ethoxy) -acetic acid ethyl ester (381 mg, 1.45 mM) obtained in the step (1), using the experimental method of Preparation Example 1 (4) 130 mg (0.65 mM) of the title compound were obtained in 44% yield.

NMR: ¹ H-NMR (CDCl ₃ ) δ 8.47 (2H, s), 4.23 (2H, q, J = 8 Hz), 4.22 to 3.99 (2H, m), 3.80 to 3.70 (1H, m), 3.25 to 3.20 (1H, m), 3.10-2.98 (1H, m), 1.29 (3H, t, J = 7.5 Hz), 1.20 (3H, d, J = 5 Hz)

Mass (EI) 200 (M ⁺ +1)

Production Example  11: 5-amino-3- Trifluoromethyl - Pentanoic acid  Synthesis of Ethyl Ester Hydrochloride

(One) 2-oxo-4- Trifluoromethyl Piperidine-1- Carboxylic acid  Synthesis of t-butyl ester

Sodium metaperiodate (NaIO ₄ , 2.82 g, 3.2 mM) was dissolved in 20 ml of water, then ruthenium oxide (RuO ₂ , 117 mg, 0.88 mM) was added, followed by 4-tree dissolved in ethyl acetate (35 ml). Fluoromethyl-piperidine-1-carboxylic acid t-butyl ester (660 mg, 2.6 mM) was added dropwise thereto, followed by stirring for 2 hours 20 minutes. After stirring, the mixture was diluted with excess ethyl acetate and washed once with water and brine. After drying over anhydrous magnesium sulfate, the filtrate was filtered under reduced pressure, and the residue was purified by column chromatography (2: 1 hexane: ethyl acetate) to obtain 0.63 g (yield 90%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 3.86 (1H, dd, J = 13.5, 5.5 Hz), 3.62 (1H, m), 2.6-2.8 (2H, m), 2.56 (1H, dd, J = 17, 10 Hz ), 2.1-2.2 (1H, m), 1.8-1.9 (1H, m), 1.53 (9H, s)

Mass (m / e) 290 (M + Na)

(2) 5-t- Butoxycarbonylamino -3- Trifluoromethyl - Pentanoic acid  Synthesis of Ethyl Ester

The 2-oxo-4-trifluoromethyl-piperidine-1-carboxylic acid t-butyl ester (630 mg, 2.36 mM) obtained in step (1) was dissolved in methanol, followed by sodium ethoxide (255). mg, 4.5 mM) and stirred for 15 minutes, concentrated methanol and diluted with excess ethyl acetate, and then washed once with 1 N aqueous hydrochloric acid solution and brine. After drying over anhydrous magnesium sulfate, the filtrate was filtered under reduced pressure. The residue was purified by column chromatography (5: 1 hexanes: ethyl acetate) to give 0.48 g (65% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 4.76 (1H, br s), 4.17 (2H, q, J = 7.0 Hz), 3.1-3.3 (2H, m), 2.7-2.8 (1H, m), 2.62 (1H, dd, J = 16, 5 Hz), 2.4 (1H, dd, J = 16, 8 Hz), 1.9 (1H, m), 1.6 (1H, m), 1.43 (9H, s), 1.26 (3H, t , J = 7.0 Hz)

Mass (m / e) 336 (M + Na)

(3) 5-amino-3- Trifluoromethyl - Pentanoic acid  Synthesis of Ethyl Ester Hydrochloride

5-t-butoxycarbonylamino-3-trifluoromethyl-pentanoic acid ethyl ester (477 mg, 1.5 mM) obtained in the step (2) was reacted with ethyl acetate / hydrochloric acid and stirred for 35 minutes. Concentration and solidification with diethyl ether gave 0.220 g (68% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 4.16 (2H, q, J = 7.0 Hz), 3.04 (2H, t, J = 8.0 Hz), 2.9 (1H, m), 2.70 (1H, dd, J = 16, 5 Hz), 2.55 (1H, dd, J = 17, 8 Hz), 2.0-2.1 (1H, m), 1.8-1.9 (1H, m), 1.26 (3H, t, J = 7.0 Hz)

Mass (m / e) 214 (M + 1)

Production Example  12: 5-amino-4,4- Difluoro - Pentanoic acid methyl  Synthesis of Ester Hydrochloride

(One) 3,3- Difluoro Piperidine-1- Carboxylic  Synthesis of Acid t-Butyl Ester

3-oxo-piperidine-1-carboxylic acid t-butyl ester (400 mg, 2.0 mM) was dissolved in dichloromethane and the temperature was lowered to -78 ° C, followed by diethylaminosulfurtrifluoride (DAST, 0.53 ml, 4.0 mM) was added dropwise and stirred for 19 hours. At this time, the temperature was slowly raised to room temperature. Water (about 0.3 ml) was added, concentrated, and the residue was purified by column chromatography (10: 1 hexane: ethyl acetate) to obtain 0.29 g (64% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 3.61 (2H, t, J = 11 Hz), 3.4 (2H, m), 1.9-2.0 (2H, m), 1.7-1.8 (2H, m), 1.45 (9H, s )

Mass (m / e) 244 (M + Na)

(2) 5,5- Difluoro -2-oxo-piperidine-1- Carboxylic acid  Synthesis of t-butyl ester

Sodium metaperiodate (NaIO ₄ , 0.53 g, 2.5 mM) was dissolved in 4 ml of water, then ruthenium oxide (RuO ₂ , 22 mg, 0.17 mM) was added and dissolved in ethyl acetate (7 ml). 3,3-Difluoro-piperidine-1-carboxylic acid t-butyl ester (110 mg, 0.5 mM) obtained in 1) was added dropwise and stirred for 21 hours. After stirring, the mixture was diluted with excess ethyl acetate and washed once with water and brine. After drying over anhydrous magnesium sulfate, the filtrate was filtered under reduced pressure. The residue was purified by column chromatography (2: 1 hexanes: ethyl acetate) to give 91 mg (yield 78%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 3.97 (2H, t, J = 13 Hz), 2.66 (2H, t, J = 7.0 Hz), 2.3-2.4 (2H, m), 1.53 (9H, s)

Mass (m / e) 258 (M + Na)

(3) 5-t- Butoxycarbonylamino -4,4- Difluoro - Pentanoic acid methyl  Ester synthesis

5,5-Difluoro-2-oxo-piperidine-1-carboxylic acid t-butyl ester (91 mg, 0.39 mM) obtained in step (2) was dissolved in methanol, and then sodium methoxide ( 42 mg, 0.78 mM) was added thereto, stirred for 20 minutes, the methanol was concentrated, diluted with excess ethyl acetate, and washed once with 1 N aqueous hydrochloric acid solution and brine. After drying over anhydrous magnesium sulfate, the filtrate was filtered under reduced pressure. The residue was purified by column chromatography (2: 1 hexanes: ethyl acetate) to give 73 mg (71% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 4.83 (1H, br s), 3.69 (3H, s), 3.4-3.6 (2H, m), 2.55 (2H, t, J = 8 Hz), 2.1-2.3 (2H, m), 1.44 (9H, s)

Mass (m / e) 290 (M + Na)

(4) 5-amino-4,4- Difluoro - Pentanoic acid methyl  Synthesis of Ester Hydrochloride

5-t-butoxycarbonylamino-4,4-difluoro-pentanoic acid methyl ester (73 mg, 0.27 mM) obtained in the step (3) was reacted with ethyl acetate / hydrochloric acid and stirred for 25 minutes. Concentrated and then solidified with diethyl ether to give 40 mg (yield 88%) of the title compound.

¹ H NMR (CD ₃ OD) δ 3.68 (3H, s), 3.48 (2H, t, J = 15 Hz), 2.59 (2H, t, J = 7.5 Hz), 2.3-2.4 (2H, m)

Mass (m / e) 168 (M + 1)

Production Example  13: 3S-t- Butoxycarboxylic amino -4-hydroxy- Butyric acid  Of benzyl ester synthesis

6.46 g (20 mM) of 2S-t-butoxycarboxyamino-succinic acid 4-benzyl ester was dissolved in tetrahydrofuran, and the temperature was lowered to 0C. 1.9 ml (20 mM) of ethyl chloroformate, 2.79 triethylamine After dropwise addition of ml, after 30 minutes, sodium borohydride 1.5 g (40 mM) was added and methanol was slowly poured and stirred for 1 hour. Then, the mixture was diluted with excess ethyl acetate and washed once with 1 N aqueous HCl solution and brine. After drying over anhydrous magnesium sulfate, the filtrate was filtered under reduced pressure. The residue was purified by column chromatography (4: 1 hexanes: ethyl acetate) to give 4.44 g (72% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 7.3-7.4 (5H, m), 5.21 (1H, d, J = 8 Hz), 5.12 (2H, s), 4.0 (1H, m), 3.69 (2H, d, J = 5 Hz), 2.67 (2H, d, J = 5.5 Hz), 1.42 (9H, s)

Mass (m / e) 310 (M + 1)

Production Example  14: 3S-t- Butoxycarboxylic amino -4-oxo- Butyric acid  Synthesis of Benzyl Ester

0.31 g (1.0 mM) of 3S-t-butoxycarboxyamino-4-hydroxy-butyric acid benzyl ester obtained in Preparation Example 13 was dissolved in dichloromethane, and 6 ml of Dess-Martin sample (˜0.3 M) was added dropwise. Stir for 4 hours. After concentration the residue was purified by column chromatography (2: 1 hexanes: ethyl acetate) to give 0.23 g (75% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 9.64 (1H, s), 7.3-7.4 (5H, m), 5.6 (1H, d, J = 7.5 Hz), 5.12 (2H, s), 4.35 (1H, m), 3.05 (1H, dd, J = 15.0, 5.0 Hz), 2.88 (1H, dd, J = 15.0, 5.0 Hz), 1.44 (9H, s)

Mass (m / e) 308 (M + 1)

Production Example  15: 3S- t-butoxycarboxyamino -4- (2-hydroxy- Ethylamino )- Butyric acid  Synthesis of Benzyl Ester

0.68 g (2.2 mM) of 3S-t-butoxycarboxylic amino-4-oxo-butyric acid benzyl ester obtained in Preparation Example 14 was dissolved in dichloroethane, and then the temperature was lowered to 0 ° C., 2-amino ethanol (130 μl, 2.2 mM) was added dropwise and stirred for 30 minutes. Then 1.4 g (6.6 mM) of sodium triacetoxyborohydride were added and stirred for an additional 10 hours. The reaction solution was diluted with dichloromethane, washed with saturated aqueous sodium hydrocarbon solution, dried over anhydrous magnesium sulfate, and the filtrate was filtered under reduced pressure. After concentration the residue was purified by column chromatography (1: 1 hexanes: ethyl acetate-> 10: 1 CH ₂ Cl ₂ : MeOH) to give 0.14 g (yield 18%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 7.3-7.4 (5H, m), 5.8-6.1 (1H, m), 5.12 (2H, s), 4.15-4.35 (1H, m), 3.7-3.8 (2H, m) , 2.9-3.15 (4H, m), 2.6-2.8 (2H, m), 1.42 (9H, s)

Mass (m / e) 353 (M + 1)

Production Example  16: 3S- t-butoxycarboxyamino -4- (2-oxo- Oxazolidine -3 days)- Butyric acid  Synthesis of Benzyl Ester

140 mg (0.4 mM) of 3S-t-butoxycarboxyamino-4- (2-hydroxy-ethylamino) -butyric acid benzyl ester obtained from Preparation Example 15 was dissolved in dichloromethane, and the temperature was decreased to 0 ° C. and N , N-diisopropylethylamine (280 μl, 1.6 mM) and dimethylaminopyridine (49 mg, 0.4 mM) were added, followed by dropwise addition of phosphine (20% toluene, 0.4 g, 0.6 mM) for 2 hours 40 minutes. Was stirred. Then, the mixture was diluted with dichloromethane, washed with brine, dried over anhydrous magnesium sulfate, and the filtrate was filtered under reduced pressure. After concentration, the residue was purified by column chromatography (1: 1 hexanes: ethyl acetate) to give 30 mg (20% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 7.3-7.4 (5H, m), 5.12 (2H, s), 5.1 (1H, m), 4.3 (2H, m), 4.2 (1H, m), 3.76 (1H, m ), 3.5 (2H, m), 3.22 (1H, m), 2.63 (1H, dd, J = 16, 5.5 Hz), 2.58 (1H, dd, J = 16, 6.5 Hz), 1.41 (9H, s)

Mass (m / e) 379 (M + 1)

Production Example  17: [3-oxo-1- (2-oxo-oxazolidin-3-ylmethyl) -3- (3-trifluoromethyl-5, 6-dihydro-8H- [1, 2, 4] Triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-butyl  Synthesis of Ester

30 mg (0.079 mM) of 3S-t-butoxycarboxyamino-4- (2-oxo-oxazolidin-3-yl) -butyric acid benzyl ester obtained from Preparation Example 16 was dissolved in methanol, followed by palladium / charcoal ( Pd / C) 3 mg was added, and it stirred for 3 hours and 40 minutes in hydrogen atmosphere. After confirming the reaction, it was filtered through Celite, washed with methanol, concentrated and immediately proceeded with 3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3 -a] pyrazine (15 mg, 0.079 mM) was added and then dissolved in dichloromethane. After the temperature was lowered to 0 ° C., HOBT (13 mg, 0.095 mM) was added, and after 10 minutes of stirring, EDC (23 mg, 0.12 mM) was added, the ice water container was removed, and the concentrated residue was stirred for about 17 hours. Purification by tilc (prep-TLC, 10: 1 CH ₂ Cl ₂ : MeOH) gave 21 mg (57% yield of two steps) of the title compound.

¹ H NMR (CDCl ₃ ) δ 5.6-5.8 (1H, m), 4.9-5.1 (2H, m), 4.0-4.4 (6H, m), 3.6-3.8 (2H, m), 3.3-3.5 (2H, m), 2.6-2.9 (2H, m), 1.39 (9H, s)

Mass (m / e) 463 (M + 1)

Example  1: 3- [2S-amino-4-oxo-4- (3- Trifluoromethyl -5,6- Dehydro -8H- [1,2,4] Triazolo Synthesis of [4,3-a] pyrazin-7-yl) -butyl] -oxazolidin-2-one

[3-oxo-1- (2-oxo-oxazolidin-3-ylmethyl) -3- (3-trifluoromethyl-5,6-dihydro-8H- [1,2] obtained from Preparation Example 17 21 mg (0.045 mM) of triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-butyl ester was dissolved in ethyl acetate / hydrochloric acid and stirred for about 30 minutes. And then concentrated to give a white solid. This solid was washed with diethyl ether and dried to give 15 mg (91%) of the title compound.

¹ H NMR (CD ₃ OD) δ 5.06 (2H, s), 4.4 (3H, m), 4.26 (1H, m), 4.05-4.15 (2H, m), 3.9 (1H, m), 3.5-3.8 ( 4H, m), 3.0-3.1 (1H, m), 2.85-2.95 (1H, m),

Mass (m / e) 363 (M + l).

Production Example  18: 3S- t-butoxycarboxyamino -4- (2-hydroxy- Propylamino )- Butyric acid  Synthesis of Benzyl Ester

0.68 g (2.2 mM) of 3S-t-butoxycarboxyamino-4-oxo-butyric acid benzyl ester obtained in Preparation Example 14 was dissolved in dichloroethane, and then the temperature was lowered to 0 ° C., 2-aminoethanol (170 μl, 2.2 mM) was added dropwise and stirred for 30 minutes. Then 1.4 g (6.6 mM) of sodium triacetoxyborohydride were added and stirred for an additional 10 hours. Diluted with dichloromethane, washed with saturated aqueous sodium hydrocarbon solution, dried over anhydrous magnesium sulfate, and the filtrate was filtered under reduced pressure. After concentration the residue was purified by column chromatography (1: 1 hexanes: ethyl acetate → 10: 1 CH ₂ Cl ₂ : MeOH) to give 0.36 g (45% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 7.3-7.4 (5H, m), 5.8-6.0 (1H, m), 5.10 (2H, m), 3.9-4.0 (1H, m), 2.5-3.1 (6H, m) , 1.40 (9H, s), 1.15 (3H, d, J = 7 Hz)

Mass (m / e) 367 (M + 1)

Production Example  19: 3S- t-butoxycarboxyamino -4- (5- methyl 2-oxo- Oxazolidine -3 days)- Boutiric Synthesis of Acid Benzyl Esters

360 mg (0.98 mM) of 3S-t-butoxycarboxyamino-4- (2-hydroxy-propylamino) -butyric acid benzyl ester obtained from Preparation Example 18 was dissolved in dichloromethane, and the temperature was lowered to 0 ° C. and N , N-diisopropylethylamine (680 μl, 3.92 mM) and dimethylaminopyridine (120 mg, 0.98 mM) were added, followed by dropwise addition of phosphine (20% toluene, 1.0 g, 1.5 mM) for 2 hours 40 Stir for minutes. The reaction solution was diluted with dichloromethane, washed with brine, dried over anhydrous magnesium sulfate, and the filtrate was filtered under reduced pressure. After concentration the residue was purified by column chromatography (1: 1 hexanes: ethyl acetate) to give 120 mg (31% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 7.3-7.4 (5H, m), 5.10 (2H, s), 5.10 (1H, m), 4.55-4.65 (1H, m), 4.1-4.2 (1H, m), 3.0 -3.8 (3H, m), 2.5-2.8 (2H, m), 1.41 (12H, m)

Mass (m / e) 393 (M + 1)

Production Example  20: [1- (5-methyl-2-oxo-oxazolidin-3-ylmethyl) -3-oxo-3- (3-trifluoromethyl-5,6-dihydro-8H- [1, Synthesis of 2,4] triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-butyl ester

120 mg (0.31 mM) of 3S-t-butoxycarboxyamino-4- (5-methyl-2-oxo-oxazolidin-3-yl) -butyric acid benzyl ester obtained in Preparation Example 19 was dissolved in methanol. 12 mg of palladium / charcoal (Pd / C) was put, and it stirred for 3 hours and 40 minutes in hydrogen atmosphere. After confirming the completion of the reaction, filtered through syllite, washed with methanol, concentrated and immediately added amine (59 mg, 0.31 mM) and dissolved in dichloromethane. After the temperature was lowered to 0 ° C., HOBT (50 mg, 0.37 mM) was added and stirred for 10 minutes. Then, EDC (88 mg, 0.47 mM) was added, the ice water container was removed, and the concentrated residue was stirred for about 17 hours. Purification by prep-TLC (prep-TLC, 10: 1 CH ₂ Cl ₂ : MeOH) gave 88 mg (60% yield of two steps) of the title compound.

¹ H NMR (CDCl ₃ ) δ 5.6-5.9 (1H, m), 4.9-5.1 (2H, m), 4.6-4.8 (1H, m), 3.9-4.3 (5H, m), 3.6-3.8 (1H, m), 3.1-3.5 (3H, m), 2.5-2.9 (2H, m), 1.40 (12H, m)

Mass (m / e) 477 (M + 1)

Example  2: 3- [2S-amino-4-oxo-4- (3- Trifluoromethyl -5,6- Dehydro -8H- [1,2,4] Triazolo Synthesis of [4,3-a] pyrazin-7-yl) -butyl] -5-methyl-oxazolidin-2-one

[1- (5-Methyl-2-oxo-oxazolidin-3-ylmethyl) -3-oxo-3- (3-trifluoromethyl-5, 6-dihydro-8H- obtained from Preparation Example 20 Dissolve 88 mg (0.045 mM) of [1,2,4] triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-butyl ester in ethyl acetate / hydrochloric acid solution After stirring for about 30 minutes, it was concentrated to obtain a white solid. This solid was washed with diethyl ether and dried to give 42 mg (yield 60%) of the title compound.

¹ H NMR (CD ₃ OD) δ 5.1-5.2 (2H, m), 4.7-4.8 (1H, m), 4.45 (1H, m), 4.3 (1H, m), 4.0-4.2 (3H, m), 3.8-3.9 (2H, m), 3.4-3.7 (2H, m), 2.9-3.1 (2H, m), 1.41 (3H, m)

Mass (m / e) 377 (M + 1)

Production Example  21: 3S- t-butoxycarboxyamino -4-( t-butyl -dimethyl- Silanyloxy )- Butyric acid  Synthesis of Benzyl Ester

4.0 g (12.9 mM) of 3S-t-butoxycarboxylicamino-4-hydroxy-butyric acid benzyl ester obtained in Preparation Example 13 was dissolved in dimethylformamide, followed by imidazole (2.34 g, 15.5 mM) and t-butyl Dimethylsilyl chloride (2.34 g, 32.3 mM) was added thereto, followed by stirring for 2 hours. Then, diluted with excess ethyl acetate and washed once each with water and brine. After drying over anhydrous magnesium sulfate, the filtrate was filtered under reduced pressure, and the residue was purified by column chromatography (5: 1 hexane: ethyl acetate) to obtain 4.0 g (yield 73%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 7.3-7.4 (5H, m), 5.21 (1H, d, J = 8 Hz), 5.08 (1H, m), 4.0-4.1 (1H, m), 3.6-3.7 (2H, m), 2.6-2.7 (2H, m), 1.42 (9H, s), 0.86 (9H, s), 0.01 (6H, s)

Mass (m / e) 424 (M + 1)

Production Example  22: [1- (t-butyl-dimethyl-silanyloxymethyl) -3-oxo-3- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-  Synthesis of Butyl Ester

(1) of 3S-t- butoxycarbonylamino- 4- (t-butyl-dimethyl- silanyloxy ) -butanoic acid Synthesis

1.0 g (2.36 mM) of 3S-t-butoxycarboxyamino-4- (t-butyl-dimethyl-silanyloxy) -butyric acid benzyl ester obtained in Production Example 21 was dissolved in methanol, followed by palladium / charcoal (Pd / 120 mg of C) was put, and it stirred for 3 hours and 25 minutes in hydrogen atmosphere. After confirming the completion of the reaction, it was filtered through sylite, washed with methanol and concentrated.

¹ H NMR (CDCl ₃ ) δ 5.10 (1H, m), 4.02 (1H, m), 3.6-3.7 (2H, m), 2.61 (2H, m), 1.43 (9H, s), 0.88 (9H, s ), 0.04 (6H, s)

Mass (m / e) 356 (M + Na)

(2) [One-( t-butyl -dimethyl- Silanyloxymethyl ) -3-oxo-3- (3- Trifluoromethyl -5,6- Dehydro -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-butyl  Synthesis of Ester

3-trifluoromethyl-5, in 3S-t-butoxycarboxyamino-4- (t-butyl-dimethyl-silanyloxy) -butyric acid (333 mg, 1 mM) obtained in step (1) 6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine (192 mg, 1 mM) was added and dissolved in dichloromethane. Lower the temperature to 0 ° C, add HOBT (162 mg, 1.2 mM), stir for 10 minutes, add EDC (288 mg, 1.5 mM), remove the ice water container, stir for about 13 hours, and concentrate the concentrated residue. Purification by column chromatography (1: 1 hexanes: ethyl acetate) gave 0.27 g (53% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 5.1-5.3 (1H, m), 4.9-5.1 (2H, m), 3.9-4.3 (4H, m), 3.7-3.8 (2H, m), 2.6-2.9 (2H, m), 1.40 (9H, s), 0.87 (9H, s), 0.03 (6H, s)

Mass (m / e) 508 (M + 1)

Production Example  23: [1-formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -propyl] -1S-carbamic acid t-butyl  Synthesis of Ester

(One) [One- Hydroxymethyl -3-oxo-3- (3- Trifluoromethyl -5,6- Dehydro -8H- [1,2,4] T Riazolo [ 4,3-a] pyrazine -7-yl) -propyl] -1S- Carbamic acid  Synthesis of t-butyl ester

[1- (t-Butyl-dimethyl-silanyloxymethyl) -3-oxo-3- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4 obtained from Preparation Example 22 ] 2.3 g (4.53 mM) of triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-butyl ester was dissolved in tetrahydrofuran and then tetrabutylammonium fluoride (9 ml). , 1 M in THF) was added dropwise and stirred for about 12 minutes. Then, diluted with excess ethyl acetate and washed once with water and brine. After drying over anhydrous magnesium sulfate, the filtrate was filtered under reduced pressure, and the residue was purified by column chromatography (15: 1 CH ₂ Cl ₂ : MeOH) to obtain [1-hydroxymethyl-3-oxo-3- (3 -Trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-butyl ester 1.78 g (99% yield) were obtained.

¹ H NMR (CDCl ₃ ) δ 5.3-5.5 (1H, m), 5.0-5.2 (2H, m), 3.9-4.3 (4H, m), 3.6-3.8 (2H, m), 2.7-3.0 (2H, m), 1.41 (9H, s)

Mass (m / e) 394 (M + 1)

(2) [One- Formyl -3-oxo-3- (3- Trifluoromethyl -5,6- Dehydro -8H- [1,2,4] Triazole in[ 4,3-a] pyrazine -7-yl) -propyl] -1S- Carbamic acid  Synthesis of t-butyl ester

[1-hydroxymethyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3] obtained in step (1). -a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-butyl ester (500 mg, 1.27 mM) was dissolved in dichloromethane and 10 ml of Dess-Martin sample (~ 0.3 M) was added dropwise. Stir for 2 hours 40 minutes. After concentration the residue was purified by column chromatography (1: 2 hexanes: ethyl acetate ethyl acetate) to give 0.33 g (66% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 9.67 (1H, s), 5.7-5.9 (1H, m), 4.9-5.1 (2H, m), 3.9-4.5 (5H, m), 3.1-3.2 (1H, m) , 2.9-3.0 (1H, m), 1.42 (9H, s)

Mass (m / e) 392 (M + 1)

Production Example  24: [3-oxo-1- (2-oxo-piperidin-1-ylmethyl) -3- (3-trifluoromethyl-5,6-di Heathrow -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-butyl  Synthesis of Ester

[1-formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) 5-Amino-pentanoic acid methyl ester (33 mg, 0.2 mM) was added to 77 mg (0.2 mM) of -propyl] -1S-carbamic acid t-butyl ester, dissolved in dichloroethane and stirred for 30 minutes. Then 83 mg (0.4 mM) of sodium triacetoxyborohydride were added and stirred for about 1 hour 40 excess. The solution was heated for about 7 hours (80 ° C.), concentrated, and the residue was purified by prep-TLC (10: 1 CH ₂ Cl ₂ : MeOH) to obtain about 20 mg of the title compound (two steps). Yield 21%).

¹ H NMR (CD ₃ OD) δ 6.5 (1H, m), 4.9-5.1 (2H, m), 4.0-4.4 (5H, m), 3.35-3.5 (3H, m), 2.6-2.8 (2H, m ), 2.28 (2H, t, J = 6.0 Hz), 1.7-1.8 (4H, m), 1.36 (9H, s)

Mass (m / e) 475 (M + 1)

Example  3: 1- [2S-amino-4-oxo-4- (3- Trifluoromethyl -5,6- Dehydro -8H- [1,2,4] Triazolo Synthesis of [4,3-a] pyrazin-7-yl) -butyl] -piperidin-2-one

[3-oxo-1- (2-oxo-piperidin-1-ylmethyl) -3- (3-trifluoromethyl-5,6-dihydro-8H- [1,2] obtained from Preparation Example 24 Dissolve 88 mg (0.045 mM) of triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-butyl ester in ethyl acetate / hydrochloric acid solution and stir for about 30 minutes After concentration, the residue was purified by prep-TLC (10: 1 CH ₂ Cl ₂ : MeOH) to give 10.4 mg (66% yield) of the title compound.

¹ H NMR (CD ₃ OD) δ 4.9-5.1 (2H, m), 4.6 (1H, br), 4.0-4.4 (4H, m), 3.8-3.9 (2H, m), 3.35-3.5 (2H, m ), 2.8-3.0 (2H, m), 2.0-2.4 (2H, m), 1.8-1.9 (4H, m),

Mass (m / e) 375 (M + 1)

Production Example  25: [1- (4-Methyl-2-oxo-pyrrolidin-1-ylmethyl) -3-oxo-3- (3-trifluoromethyl-5, 6-dihydro-8H- [1, 2,4] triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t- Synthesis of Butyl Ester

[1-formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine obtained from Preparation Example 23 4-amino-3-methyl-butanoic acid methyl ester (21 mg, 0.13 mM) was added to 50 mg (0.13 mM) of -7-yl) -propyl] -1S-carbamic acid t-butyl ester. It was dissolved in ethane and stirred for 30 minutes. Then 83 mg (0.4 mM) of sodium triacetoxyborohydride were added and stirred for an additional 20 hours. The solution was concentrated and the residue was purified by prep-TLC (10: 1 CH ₂ Cl ₂ : MeOH) to give about 18 mg (30% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 5.7-6.0 (1H, m), 4.8-5.1 (2H, m), 3.9-4.4 (5H, m), 3.3-3.7 (3H, m), 3.0-3.1 (1H, m), 2.3-2.9 (4H, m), 1.9-2.0 (1H, m), 1.40 (9H, s), 1.09 (3H, d, J = 5 Hz)

Mass (m / e) 475 (M + 1)

Example  4: 1- [2S-amino-4-oxo-4- (3- Trifluoromethyl -5,6- Dehydro -8H- [1,2,4] Triazolo Synthesis of [4,3-a] pyrazin-7-yl) -butyl] -4-methyl-pyrrolidin-2-one

[1- (4-Methyl-2-oxo-pyrrolidin-1-ylmethyl) -3-oxo-3- (3-trifluoromethyl-5 obtained from Preparation Example 25 in the same manner as in Example 3 18 mg of 6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-butyl ester with ethyl acetate / hydrochloric acid Reaction with the liquid gave 5.8 mg of the title compound (yield 37%).

¹ H NMR (CD ₃ OD) δ 4.9-5.1 (2H, m), 4.0-4.3 (4H, m), 3.3-3.7 (4H, m), 3.0-3.1 (1H, m), 2.4-2.8 (4H , m), 1.9-2.0 (1H, m), 1.1 (3H, m),

Mass (m / e) 375 (M + 1)

Production Example  26: [1- (3-Fluoro-2-oxo-pyrrolidin-1-ylmethyl) -3-oxo-3- (3-trifluoro methyl -5,6- Dehydro -8H- [1,2,4] Triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S- Carbamic Synthesis of Acid t-Butyl Ester

[1-formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine obtained from Preparation Example 23 -7-yl) -propyl] -1S-carbamic acid t-butyl ester 39 mg (0.1 mM) with 4-amino-2-fluoro-butyric acid methyl ester hydrochloride (17 mg, 0.1 mM) (Preparation Example 3 Product) and 42 mg (0.2 mM) of sodium triacetoxyborohydride to give 5.8 mg (yield 37%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 5.7-5.9 (1H, m), 4.9-5.1 (3H, m), 3.8-4.3 (5H, m), 3.3-3.7 (4H, m), 2.4-2.8 (3H, m), 2.1-2.2 (1H, m), 1.40 (9H, s),

Mass (m / e) 479 (M + 1)

Example  5: 1- [2S-amino-4-oxo-4- (3- Trifluoromethyl -5,6- Dehydro -8H- [1,2,4] Triazolo Synthesis of [4,3-a] pyrazin-7-yl) -butyl] -4,4-dimethyl-pyrrolidin-2-one

[1- (3-Fluoro-2-oxo-pyrrolidin-1-ylmethyl) -3-oxo-3- (3-trifluoromethyl-) obtained from Production Example 26 in the same manner as in Example 3. 15 mg of 5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-butyl ester ethyl acetate / Reaction with hydrochloric acid gave 5.9 mg of the title compound (yield 45%).

¹ H NMR (CD ₃ OD) δ 4.9-5.1 (2H, m), 4.0-4.35 (4H, m), 3.4-3.7 (3H, m), 3.3-3.4 (2H, m), 2.6-2.9 (2H , m), 2.1-2.3 (2H, m), 1.9-2.0 (1H, m), 1.16 (3H, s), 1.15 (3H, s)

Mass (m / e) 389 (M + 1)

Example  6: 1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] Riazolo Synthesis of [4,3-a] pyrazin-7-yl) -butyl] -3-fluoro-pyrrolidin-2-one

[1-formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine obtained from Preparation Example 23 77 mg (0.2 mmol) of -7-yl) -propyl] -1S-carbamic acid t-butyl ester was added to 4-amino-butyric acid methyl ester (23 mg, 0.2 mM) and dissolved in dichloroethane, Stir for 30 minutes. Then 84 mg (0.4 mM) of sodium triacetoxyborohydride were added and stirred for 2 hours. 15 mg of the title compound was obtained in the same manner as in Example 3 after concentration (yield 21%).

¹ H NMR (CD ₃ OD) δ 5.0-5.3 (3H, m), 4.2-4.4 (2H, m), 4.0-4.2 (2H, m), 3.4-3.7 (5H, m), 2.5-2.8 (3H , m), 2.1-2.3 (1H, m)

Mass (m / e) 379 (M + 1)

¹ H NMR (CD ₃ OD) δ 5.00-4.95 (2H, m), 4.31-4.22 (2H, m), 4.10-4.01 (2H, m), 3.74 (1H, brs), 3.53-3.41 (3H, m ), 2.89-2.72 (2H, m), 2.37-2.34 (2H, m), 2.08-2.05 (2H, m), 1.27 (2H, brs).

Mass (m / e) 361 (M + 1)

Production Example  27: [1- (3-Fluoro-2-oxo-piperidin-1-ylmethyl) -3-oxo-3- (3-trifluoro methyl -5,6- Dehydro -8H- [1,2,4] Triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S- Carbamic Synthesis of Acid t-Butyl Ester

[1-formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine obtained from Preparation Example 23 -7-yl) -propyl] -1S-carbamic acid t-butyl ester 90 mg (0.1 mM) with 5-amino-2-fluoro-pentanoic acid methyl ester (43 mg, 0.1 mM) and sodium triacetox 98 mg (0.2 mM) of ciborohydride was reacted to give 24 mg of the title compound (yield 21%).

1 H NMR (CDCl ₃ ) δ 5.8-6.1 (1H, m), 4.6-5.2 (3H, m), 3.8-4.4 (5H, m), 3.2-3.6 (4H, m), 2.6-3.0 (2H, m ), 1.7-2.1 (4H, m), 1.40 (9H, s),

Mass (m / e) 493 (M + 1)

Example  7: 1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] Riazolo [4,3- a Synthesis of Pyrazin-7-yl) -butyl] -pyrrolidin-2-one

[1- (3-Fluoro-2-oxo-piperidin-1-ylmethyl) -3-oxo-3- (3-trifluoromethyl-5,6-dihydro-8H obtained from Preparation Example 27 24 mg of [[1,2,4] triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-butyl ester was reacted in the same manner as in Example 3 6 mg of the title compound were obtained (yield 31%).

¹ H NMR (CD ₃ OD) δ 4.9-5.1 (2H, m), 4.7-4.9 (1H, m), 4.2-4.4 (2H, m), 4.0-4.2 (2H, m), 3.7-3.8 (1H , m), 3.3-3.6 (4H, m), 2.7-3.0 (2H, m), 1.8-2.2 (4H, m)

Mass (m / e) 393 (M + 1)

Production Example  28: [1- (3- methyl 2-oxo- Pyrrolidine -One- Methyl ) -3-oxo-3- (3- Trifluoromethyl Synthesis of -5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-butyl ester

[1-formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine obtained from Preparation Example 25 -7-yl) -propyl] -1S-carbamic acid t-butyl ester 75 mg (0.1 mM) with 4-amino-2-methyl-butanoic acid methyl ester (32 mg, 0.1 mM) and sodium triacetoxybo 81 mg (0.2 mM) of low hydride was reacted in the same manner as in Preparation 24 to obtain 24 mg of the title compound (yield 22%).

¹ H NMR (CDCl ₃ ) δ 5.8-6.0 (1H, m), 4.8-5.1 (2H, m), 3.8-4.3 (5H, m), 3.3-3.5 (4H, m), 2.5-2.9 (2H, m), 2.1-2.4 (2H, m), 1.5-1.6 (1H, m), 1.40 (9H, s), 1.09-1.1 (3H, m)

Mass (m / e) 475 (M + 1)

Example  8: 1- [2S-amino-4-oxo-4- (3- Trifluoromethyl -5,6- Dehydro -8H- [1,2,4] Triazolo [4,3-a] pyrazin-7-yl) -butyl] -3 Fluoro Synthesis of -piperidin-2-one

[1- (3-Fluoro-2-oxo-pyrrolidin-1-ylmethyl) -3-oxo-3- (3-trifluoromethyl-) obtained from Preparation Example 28 in the same manner as in Example 3. 24 mg of 5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-butyl ester ethyl acetate / Reaction with hydrochloric acid in the same manner as in Example 3 gave 4.5 mg of the title compound (yield 29%).

¹ H NMR (CD ₃ OD) δ 4.9-5.1 (2H, m), 4.2-4.4 (2H, m), 4.0-4.2 (2H, m), 3.6-3.7 (1H, m), 3.4-3.5 (4H , m), 2.6-2.9 (2H, m), 2.2-2.5 (2H, m), 1.6-1.7 (1H, m), 1.3 (1H, m), 1.1-1.2 (3H, m)

Mass (m / e) 375 (M + 1)

Production Example  29: [1- (4-Methyl-2-oxo-2,5-dihydro-pyrrol-1-ylmethyl) -3-oxo-3- (3-triflu Oromethyl -5,6- Dehydro -8H- [1,2,4] Triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S- Carr Synthesis of Bamic Acid t-Butyl Ester

[1-formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine obtained from Preparation Example 23 -7-yl) -propyl] -1S-carbamic acid t-butyl ester 85 mg (0.22 mM) with 4-amino-3-methyl-2-butenoic acid (36 mg, 0.22 mM) and sodium triacetoxybo 92 mg (0.44 mM) of low hydride were reacted to give 34 mg of the title compound (yield 33%).

¹ H NMR (CDCl ₃ ) δ 5.9-6.2 (1H, m), 5.72 (1H, m), 4.9-5.1 (2H, m), 3.9-4.4 (7H, m), 3.6-3.7 (1H, m) , 3.4-3.5 (1H, m), 2.7-2.9 (1H, m), 2.5-2.6 (1H, m), 2.04 (3H, s), 1.38 (9H, m)

Mass (m / e) 473 (M + 1)

Example  9: 1- [2S-amino-4-oxo-4- (3- Trifluoromethyl -5,6- Dehydro Synthesis of -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) -butyl] -4-methyl-1,5-dihydro-pyrrole-2-one

[1- (4-Methyl-2-oxo-2,5-dihydro-pyrrol-1-ylmethyl) -3-oxo-3- (3-tri, obtained from Preparation Example 29 in the same manner as in Example 3. Fluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-butyl ester 34 mg Was reacted with ethyl acetate / hydrochloric acid solution to give 25 mg of the title compound (yield 93%).

¹ H NMR (CD ₃ OD) δ 5.81 (1H, m), 5.0 (2H, m), 4.2-4.4 (2H, m), 4.0-4.1 (4H, m), 3.8-3.9 (1H, m), 3.65-3.75 (2H, m), 2.9-3.0 (1H, m), 2.75-2.85 (1H, m), 2.10 (3H, s)

Mass (m / e) 373 (M + 1)

Production Example  30: [1- (4-methyl-2-oxo-piperidin-1-ylmethyl) -3-oxo-3- (3-trifluoromethyl-5,6-dihydro-8H- [1, 2,4] triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t- Synthesis of Butyl Ester

[1-formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine obtained from Preparation Example 25 -7-yl) -propyl] -1S-carbamic acid t-butyl ester 85 mg (0.22 mM) with 5-amino-3-methyl-pentanoic acid methyl ester (39 mg, 0.22 mM) and sodium triacetoxybo 92 mg (0.44 mM) of low hydride were reacted to give 46 mg of the title compound (yield 43%).

¹ H NMR (CDCl ₃ ) δ 5.9-6.0 (1H, m), 4.8-5.1 (2H, m), 3.9-4.3 (6H, m), 3.5-3.6 (1H, m), 3.3-3.5 (3H, m), 2.7-2.9 (1H, m), 2.3-2.6 (2H, m), 1.8-1.9 (2H, m), 1.4-1.5 (1H, m), 1.39 (9H, s), 0.95 (3H, m)

Mass (m / e) 489 (M + 1)

Example  10: 1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine- 7-yl) -butyl]-4- methyl Synthesis of -piperidin-2-one

[1- (4-Methyl-2-oxo-piperidin-1-ylmethyl) -3-oxo-3- (3-trifluoromethyl-5 obtained from Preparation Example 30 in the same manner as in Example 3 46 mg of 6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-butyl ester ethyl acetate / hydrochloric acid Reaction with the liquid gave 29 mg of the title compound (yield 79%).

¹ H NMR (CD ₃ OD) δ 4.9-5.1 (2H, m), 4.2-4.4 (2H, m), 4.0-4.2 (2H, m), 3.8-3.9 (2H, m), 3.3-3.8 (3H , m), 2.8-3.0 (2H, m), 2.4 (1H, m), 1.8-2.0 (3H, m), 1.5-1.6 (1H, m), 1.0 (3H, m)

Mass (m / e) 389 (M + 1)

Production Example  31: [1- (5,5-Difluoro-2-oxo-piperidin-1-ylmethyl) -3-oxo-3- (3-triflu  Oromethyl -5,6- Dehydro -8H- [1,2,4] Triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S- Carr Synthesis of Bamic Acid t-Butyl Ester

[1-formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine obtained from Preparation Example 23 -7-yl) -propyl] -1S-carbamic acid t-butyl ester 85 mg (0.22 mM) and 5-amino-3-methyl-pentanoic acid methyl ester (44 mg, 0.22 mM) and sodium triacetoxybo 92 mg (0.44 mM) of low hydride were reacted to give 25 mg of the title compound (yield 23%).

¹ H NMR (CDCl ₃ ) 5.8-5.9 (1H, m), 4.8-5.1 (2H, m), 4.1-4.3 (4H, m), 3.9-4.0 (1H, m), 3.6-3.8 (3H, m ), 3.3-3.5 (1H, m), 2.7-2.9 (1H, m), 2.5-2.6 (2H, m), 2.4 (1H, t, J = 7.0 Hz), 2.2-2.3 (2H, m), 1.40 (9H, s)

Mass (m / e) 511 (M + 1)

Example  11: 1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine- 7-yl) -butyl] -5,5- Difluoro Synthesis of -piperidin-2-one

[1- (5,5-Difluoro-2-oxo-piperidin-1-ylmethyl) -3-oxo-3- (3-trifluoro) obtained from Preparation Example 31 in the same manner as in Example 3. 25 mg of chloromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-butyl ester Reaction with ethyl acetate / hydrochloric acid gave 7.9 mg of the title compound (yield 39%).

¹ H NMR (CD ₃ OD) δ 4.9-5.1 (2H, m), 4.2-4.4 (2H, m), 4.0-4.2 (2H, m), 3.7-3.9 (2H, m), 3.6-3.7 (2H , m), 3.4-3.5 (1H, m), 2.8 (1H, td, J = 16, 5 Hz), 2.6-2.7 (1H, m), 2.5-2.6 (2H, m), 2.3-2.4 (2H , m)

Mass (m / e) 411 (M + 1)

Production Example  32: [1- (5R-Methyl-2-oxo-piperidin-1-ylmethyl) -3-oxo-3- (3-trifluoromethyl-5,6-dihydro-8H- [1, Synthesis of 2,4] triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-butyl ester

[1-formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine obtained from Preparation Example 23 -7-yl) -propyl] -1S-carbamic acid t-butyl ester 80 mg (0.20 mM) and 5-amino-4R-methyl-pentanoic acid methyl ester (37 mg, 0.20 mM) and sodium triacetoxybo 87 mg (0.40 mM) of low hydride were reacted to obtain 33 mg of the title compound (yield 33%).

¹ H NMR (CDCl ₃ ) δ 5.9-6.0 (1H, m), 4.8-5.1 (2H, m), 3.8-4.3 (5H, m), 3.2-3.7 (3H, m), 2.9-3.1 (1H, m), 2.1-2.9 (4H, m), 1.7-2.0 (2H, m), 1.3-1.5 (1H, m), 1.40 (9H, s), 0.98 (3H, m)

Mass (m / e) 489 (M + 1)

Example  12: 1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine- 7-yl) -butyl] -5R- methyl Synthesis of -piperidin-2-one

[1- (5R-methyl-2-oxo-piperidin-1-ylmethyl) -3-oxo-3- (3-trifluoromethyl-5 obtained from Preparation Example 35 in the same manner as in Example 3 33 mg of 6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-butyl ester ethyl acetate / hydrochloric acid Reaction with the liquid gave 15.3 mg of the title compound (yield 58%).

¹ H NMR (CD ₃ OD) δ 4.9-5.1 (2H, m), 4.2-4.4 (2H, m), 4.0-4.2 (2H, m), 3.8-3.9 (1H, m), 3.7-3.8 (1H , m), 3.55-3.65 (1H, m), 3.3-3.4 (1H, m), 2.8-3.1 (3H, m), 2.3-2.4 (2H, m), 2.0-2.1 (1H, m), 1.8 -1.9 (1H, m), 1.5-1.6 (1H, m), 1.03 (3H, d, J = 6 Hz)

Mass (m / e) 389 (M + 1)

Production Example  33: [3-oxo-1- (2-oxo-4-trifluoromethyl-pyrrolidin-1-ylmethyl) -3- (3-tri Fluoromethyl -5,6- Dehydro -8H- [1,2,4] Triazolo Synthesis of [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-butyl ester

[1-formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine obtained from Preparation Example 23 -7-yl) -propyl] -1S-carbamic acid t-butyl ester 80 mg (0.20 mM) and 3-aminomethyl-4,4,4-trifluoro-butanoic acid ethyl ester (48 mg, 0.20 mM) and 87 mg (0.40 mM) of sodium triacetoxyborohydride were obtained to give 4.6 mg (yield 40%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 5.6-5.7 (1H, m), 4.8-5.1 (2H, m), 3.9-4.3 (5H, m), 3.3-3.8 (4H, m), 3.0-3.1 (1H, m), 2.4-2.9 (4H, m), 1.4 (9H, s)

Mass (m / e) 529 (M + 1)

Example  13: 1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine- Synthesis of 7-yl) -butyl] -4-trifluoromethyl-pyrrolidin-2-one

[3-oxo-1- (2-oxo-4-trifluoromethyl-pyrrolidin-1-ylmethyl) -3- (3-trifluoro) obtained from Preparation Example 33 in the same manner as in Example 3. Methyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-butyl ester 18 mg Reaction with ethyl / hydrochloric acid gave 7 mg of the title compound (yield 48%).

¹ H NMR (CD ₃ OD) δ 4.9-5.1 (2H, m), 4.2-4.4 (2H, m), 4.0-4.2 (2H, m), 3.7-3.9 (2H, m), 3.5-3.7 (3H , m), 3.3-3.4 (1H, m), 2.8-3.0 (2H, m), 2.5-2.7 (2H, m)

Mass (m / e) 429 (M + 1)

Production Example  34: [3-oxo-1- (2-oxo-4-trifluoromethyl-piperidin-1-ylmethyl) -3- (3-triple Luomethyl -5,6- Dehydro -8H- [1,2,4] Triazolo Synthesis of [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-butyl ester

[1-formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine obtained from Preparation Example 23 -7-yl) -propyl] -1S-carbamic acid t-butyl ester 80 mg (0.20 mM) and 5-amino-3-trifluoromethyl-pentanoic acid ethyl ester (51 mg, 0.20 mM) (prepared) Product of Example 11) and 87 mg (0.40 mM) of sodium triacetoxyborohydride were reacted in the same manner as in Preparation Example 24 to obtain 41 mg of the title compound (yield 37%).

¹ H NMR (CDCl ₃ ) δ 5.7-6.0 (1H, m), 4.8-5.1 (2H, m), 3.8-4.3 (5H, m), 3.3-3.7 (4H, m), 2.7-2.9 (1H, m), 2.4-2.6 (3H, m), 2.3-2.4 (1H, m), 2.1 (1H, m), 1.8 (1H, m), 1.4 (9H, s)

Mass (m / e) 543 (M + 1)

Example  14: 1- [2S-amino-4-oxo-4- (3- Trifluoromethyl -5,6- Dehydro Synthesis of -8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) -butyl] -4-trifluoromethyl-piperidin-2-one

[3-oxo-1- (2-oxo-4-trifluoromethyl-piperidin-1-ylmethyl) -3- (3-trifluoro) obtained from Preparation Example 34 by the same method as in Example 3. Methyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-butyl ester 41 mg Reaction with ethyl / hydrochloride gave 28.3 mg of the title compound (yield 85%).

¹ H NMR (CD ₃ OD) δ 4.9-5.1 (2H, m), 4.2-4.4 (2H, m), 4.0-4.2 (2H, m), 3.7-3.9 (2H, m), 3.4-3.7 (3H , m), 2.8-3.1 (3H, m), 2.5-2.7 (1H, m), 2.3-2.5 (1H, m), 2.1-2.2 (1H, m), 1.8-2.0 (1H, m), 1.3 (1H, m)

Mass (m / e) 443 (M + 1)

Production Example  35: [3-oxo-1- (2-oxo-5-trifluoromethyl-piperidin-1-ylmethyl) -3- (3-tri Fluoromethyl -5,6- Dehydro -8H- [1,2,4] Triazolo Synthesis of [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-butyl ester

[1-formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine obtained from Preparation Example 23 -7-yl) -propyl] -1S-carbamic acid t-butyl ester 286 mg (0.73 mM) and 4-aminomethyl-5,5,5-trifluoro-pentanoic acid methyl ester (172 mg, 0.73 mM) (product of Preparation 9) and 310 mg (1.46 mM) of sodium triacetoxyborohydride were reacted to give 260 mg of the title compound (yield 37%).

¹ H NMR (CDCl ₃ ) δ 5.7-6.0 (1H, m), 4.8-5.1 (2H, m), 4.1-4.3 (4H, m), 3.7-4.0 (2H, m), 3.3-3.7 (3H, m), 2.2-2.9 (5H, m), 2.0-2.1 (1H, m), 1.8-1.9 (1H, m), 1.39 (9H, s)

Mass (m / e) 543 (M + 1)

Example  15: 1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine- 7-yl) -butyl] -5 Trifluoromethyl Synthesis of -piperidin-2-one

[3-oxo-1- (2-oxo-5-trifluoromethyl-piperidin-1-ylmethyl) -3- (3-trifluoro) obtained from Preparation Example 35 in the same manner as in Example 3. Methyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-butyl ester 260 mg Reaction with ethyl / hydrochloric acid gave 15 mg of the title compound (yield 7%).

¹ H NMR (CD ₃ OD) δ 4.9-5.1 (2H, m), 4.2-4.4 (2H, m), 4.0-4.2 (2H, m), 3.8-3.9 (2H, m), 3.4-3.8 (3H , m), 2.8-3.0 (3H, m), 2.4-2.5 (2H, m), 2.0-2.1 (1H, m), 1.8-2.0 (1H, m)

Mass (m / e) 443 (M + 1)

Production Example  36: [1- (2-methyl-5-oxo-morpholin-4-ylmethyl) -3-oxo-3- (3-trifluoromethyl-5,6-dihydro-8H- [1,2 , 4] triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t- Synthesis of Butyl Ester

[1-formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine obtained from Preparation Example 23 -7-yl) -propyl] -1S-carbamic acid t-butyl ester 140 mg (0.36 mM) and (2-amino-1-methyl-ethoxy) -acetic acid ethyl ester (71 mg, 0.36 mM) ( Product of Preparation Example 10) and 151 mg (0.72 mM) of sodium triacetoxyborohydride were reacted to give 78 mg of the title compound (yield 44%).

¹ H NMR (CDCl ₃ ) δ 5.8-6.0 (1H, m), 4.8-5.1 (2H, m), 3.9-4.3 (7H, m), 3.7-3.9 (1H, m), 3.5-3.7 (1H, m), 3.1-3.5 (3H, m), 2.5-2.9 (2H, m), 1.33 (9H, s), 1.19 (3H, br s)

Mass (m / e) 491 (M + 1)

Example  16: 4- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine- Synthesis of 7-yl) -butyl] -6-methyl-morpholin-3-one

[1- (2-Methyl-5-oxo-morpholin-4-ylmethyl) -3-oxo-3- (3-trifluoromethyl-5, obtained from Preparation Example 46 in the same manner as in Example 3 78 mg of 6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazin-7-yl) -propyl] -1S-carbamic acid t-butyl ester with ethyl acetate / hydrochloric acid Reaction with gave 25.7 mg of the title compound (yield 41%).

¹ H NMR (CD ₃ OD) δ 4.9-5.1 (2H, m), 4.2-4.4 (2H, m), 4.1-4.2 (2H, m), 3.8-4.1 (4H, m), 3.68 (1H, m ), 3.2-3.5 (3H, m), 2.8-3.1 (2H, m), 1.24 (3H, d, J = 6.5 Hz)

Mass (m / e) 391 (M + 1)

Production Example  37: [1- (t-Butyl-dimethyl-silanyloxymethyl) -3- (3,4-dihydro-1H-isoquinolin-2-yl) -3-oxo-propyl] -1S- Carbamic acid  Synthesis of t-butyl ester

100 mg of 3S-t-butoxycarboxyamino-4- (t-butyl-dimethyl-silanyloxy) -butyric acid obtained from Preparation Example 22 (1) by the same method as Preparation Example 22 (2), and 3, 110 μl of 4-dihydro-1H-isoquinoline was reacted to give 349 mg of the title compound (yield 87%).

¹ H NMR (CDCl ₃ ) δ 7.1-7.3 (4H, m), 5.5-5.6 (1H, m), 4.7-4.8 (2H, m), 4.0-4.1 (1H, m), 3.6-3.9 (4H, m), 2.8-3.0 (3H, m), 2.6-2.7 (1H, m), 1.47 (9H, s), 0.92 (9H, s), 0.19 (3H, s), 0.14 (3H, s)

Mass (m / e) 449 (M + 1)

Production Example  38: [3- (3,4-Dihydro-1H-isoquinolin-2-yl) -1-formyl-3-oxo-propyl] -1S-carbamic acid t-butyl  Synthesis of Ester

(One) [3- (3,4- Dehydro -1H-isoquinolin-2-yl) -1- Hydroxymethyl Synthesis of 3-oxo-propyl] -1S-carbamic acid t-butyl ester

[1- (t-butyl-dimethyl-silanyloxymethyl) -3- (3,4-dihydro-1H-isoquinolin-2-yl obtained from Preparation Example 37 by the same method as Preparation Example 23 (1). 33-mg of 3-oxo-propyl] -1S-carbamic acid t-butyl ester with 1.6 ml of tetrabutylammonium fluoride to react [3- (3,4-dihydro-1H-isoquinolin-2-yl 250 mg of 1-hydroxymethyl-3-oxo-propyl] -1S-carbamic acid t-butyl ester were obtained.

¹ H NMR (CDCl ₃ ) δ 7.1-7.2 (4H, m), 5.5-5.6 (1H, m), 4.6-4.8 (2H, m), 3.7-4.0 (5H, m), 3.3-3.4 (2H, m), 2.7-3.0 (2H, m), 1.41 (9H, s), 0.90 (9H, s), 0.10 (6H, s)

Mass (m / e) 357 (M + Na)

(2) [3- (3,4- Dehydro -1H-isoquinolin-2-yl) -1- Formyl -3-oxo-propyl] -1S- Carbamic Synthesis of Acid t-Butyl Ester

[3- (3,4-Dihydro-1H-isoquinolin-2-yl) -1-hydroxymethyl-3-oxo-propyl] -1S of Preparation 23 (2) in the same manner as in Example 3 250 mg of the carbamic acid t-butyl ester and 10 ml of Dess-Martin sample (˜0.3 M) were reacted to obtain 180 mg of the title compound (yield 72%).

¹ H NMR (CDCl ₃ ) δ 9.72 (1H, s), 7.1-7.2 (4H, m), 5.97 (1H, m), 4.3-4.8 (4H, m), 3.6-3.8 (2H, m), 2.8 -3.0 (2H, m), 1.45 (9H, s)

Mass (m / e) 333 (M + 1)

Production Example  39: [3- (3,4- Dehydro -1H-isoquinolin-2-yl) -3-oxo-1- (2-oxo-piperidin-1-ylmethyl) -propyl] -1S- Carbamic acid  Synthesis of t-butyl ester

[3- (3,4-Dihydro-1H-isoquinolin-2-yl) -1-formyl-3-oxo-propyl] -1S-carbamic acid obtained from Preparation Example 30 in the same manner as in Preparation Example 24 60 mg (0.18 mM) of t-butyl ester, 5-amino-pentanoic acid methyl ester (30 mg, 0.18 mM) and 77 mg (0.36 mM) of sodium triacetoxyborohydride were reacted to obtain 9 mg of the title compound. (Yield 12%).

Mass (m / e) 416 (M + 1)

Example  17: Synthesis of 1- [2S-amino-4- (3,4-dihydro-1H-isoquinolin-2-yl) -4-oxo-butyl] -piperidin-2-one

[3- (3,4-Dihydro-1H-isoquinolin-2-yl) -3-oxo-1- (2-oxo-piperidine-1 obtained from Preparation Example 39 in the same manner as in Example 3 9 mg of -ylmethyl) -propyl] -1S-carbamic acid t-butyl ester was reacted with ethyl acetate / hydrochloric acid solution to give 4.4 mg of the title compound (yield 64%).

¹ H NMR (CD ₃ OD) δ 7.1-7.2 (4H, m), 4.67 (2H, d, J = 13 Hz), 3.6-3.8 (4H, m), 3.3-3.5 (3H, m), 2.8-3.0 (3H, m), 2.6-2.7 (1H, m), 2.3-2.4 (2H, m), 1.7-1.9 (4H, m)

Mass (m / e) 316 (M + 1)

Production Example  40: [3- (3,4-Dihydro-1H-isoquinolin-2-yl) -1- (4-methyl-2-oxo-pyrrolidin-1-ylmethyl) -3-oxo-propyl] -1S- Carbamic acid  Synthesis of t-butyl ester

[3- (3,4-Dihydro-1H-isoquinolin-2-yl) -1-formyl-3-oxo-propyl] -1S-carbamic acid obtained from Preparation Example 42 in the same manner as in Preparation Example 24 59 mg (0.18 mM) of t-butyl ester, 4-amino-3-methyl-butanoic acid methyl ester (30 mg, 0.18 mM) and 77 mg (0.36 mM) of sodium triacetoxyborohydride were reacted. 20 mg was obtained (yield 27%).

Mass (m / e) 416 (M + 1)

Example  18: Synthesis of 1- [2S-amino-4- (3,4-dihydro-1H-isoquinolin-2-yl) -4-oxo-butyl] -4-methyl-pyrrolidin-2-one

[3- (3,4-Dihydro-1H-isoquinolin-2-yl) -1- (4-methyl-2-oxo-pyrrolidine-1 obtained from Preparation Example 40 in the same manner as in Example 3 20 mg of -ylmethyl) -3-oxo-propyl] -1S-carbamic acid t-butyl ester was reacted with ethyl acetate / hydrochloric acid solution to give 11 mg of the title compound (yield 72%).

¹ H NMR (CD ₃ OD) δ 7.1-7.2 (4H, m), 4.67 (2H, d, J = 13 Hz), 3.6-3.8 (4H, m), 3.5 (1H, d, J = 6 Hz), 3.3-3.4 (1H, m), 3.0-3.2 (1H, m), 2.8-3.0 (3H, m), 2.6-2.8 (1H, m), 2.4-2.6 (2H, m), 2.0-2.1 (1H , m), 1.1 (3H, m)

Mass (m / e) 316 (M + 1)

Production Example  41: 3S-t- Butoxycarbonylamino -4-oxo- Butric Acid  t- Butyl ester  synthesis

Dimethylsulfuroxide (0.69 ml, 9.72 mM) was dissolved in methylene chloride (20 ml), and the temperature was lowered to -78 ° C using dry ice acetone. Oxalyl chloride (0.42 ml, 4.81 mM) was added to the solution. After slow addition, 20 minutes later, 3S-t-butoxycarbonylamino synthesized from Boc-L-Asp (O-tBu) -OH (see J. Med . Chem . 1999, 42, 3557-3571). A solution of -4-hydroxy-butyric acid t-butylester (666 mg, 2.42 mM) in dichloromethane (9 ml) was slowly added at the same temperature for 5 minutes. Then, after stirring for 20 minutes at the same temperature, triethylamine (2.0 ml, 11.7 mM) was dissolved in dichloromethane (5 ml) with the reaction solution and added dropwise for 5 minutes, and then slowly raised to -70 ℃. Dilute with diethyl ether to give 0.5 N KHSO ₄ It was washed sequentially with an aqueous solution, water and brine. The organic layer obtained at this time was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain the title compound. The compound was used for the next reaction without further purification.

¹ H NMR (CDCl ₃ ) δ 9.65 (1H, s), 5.65 (1H, brs), 4.54 (1H, brs), 2.92-2.72 (2H, m), 1.52-1.44 (18H, m)

Mass (m / e) 274 (M + 1)

Production Example  42: 3S-t- Butoxycarbonylamino -4- (2-oxo-piperidin-1-yl)- Butric Acid  Synthesis of t-butyl ester

1.80 g of 3S-t-butoxycarbonylamino-4-oxo-butyric acid t-butyl ester obtained in Production Example 41 was dissolved in 50 ml of 1,2-dichloroethane and 5 ml of 1,2-dichloroethane. 576 mg (3.44 mg) of 5-amino-pentanoic acid methyl ester hydrochloride dissolved in was added at room temperature. After stirring for 15 minutes at room temperature, 1.46 g (6.88 mM) of sodium triacetoxyborohydride was added to the suspension. After stirring for 5 hours at room temperature, the solution diluted with methylene chloride was washed sequentially with 1N aqueous hydrochloric acid solution and brine. The resulting organic solution layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting impure title compound was separated and purified through column chromatography, obtaining 568 mg (yield 46%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 5.34-5.29 (1H, m), 4.17 (1H, brs), 3.92-3.84 (1H, m), 3.51-3.46 (1H, m), 3.27-3.23 (1H, m) , 3.10-3.05 (1H, m), 2.56-2.51 (1H, m), 2.41-2.31 (3H, m), 1.82-1.75 (4H, m), 1.45 (9H, s)

Mass (m / e) 357 (M + 1)

Production Example  43: 3S-t- Butoxycarbonylamino -4- (2-oxo-piperidin-1-yl)- Butric  synthesis

(One) 3S-amino-4- (2-oxo-piperidin-1-yl)- Butric  synthesis

214 mg (0.60 mM) of t-butoxycarbonylamino-4- (2-oxo-piperidin-1-yl) -butyric acid t-butylester obtained from Preparation Example 42 was diluted with dichloromethane / trifluoro. It was dissolved in 2 ml of acetic acid (1/1) solution and stirred at room temperature for 18 hours. Excess trifluoroacetic acid and dichloromethane were removed under reduced pressure to give 280 mg of 3S-amino-4- (2-oxo-piperidin-1-yl) -butyric acid. The material was used for the next reaction without further purification.

¹ H NMR (CD ₃ OD) δ 4.00-3.77 (2H, m), 3.48-3.38 (3H, m), 2.80-2.70 (2H, s), 2.43-2.40 (2H, m), 1.89-1.82 (4H , m)

Mass (m / e) 200 (M + 1)

(2) 3S-t- Butoxycarbonylamino -4- (2-oxo-piperidin-1-yl)- Butric  synthesis

280 mg of the compound 3S-amino-4- (2-oxo-piperidin-1-yl) -butyric acid obtained in step 1 was dissolved in 10 ml of a solvent of water / 1,4-dioxane (1/1). Then 144 mg (0.66 mM) of dit-butyldicarbonate were added at room temperature. 2.3 ml of 1N sodium hydroxide aqueous solution was added to this solution, and it stirred at room temperature for 18 hours. Dichloromethane was added to the reaction mixture, diluted, and washed sequentially with 1 N aqueous hydrochloric acid solution and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. mg (61% yield) were obtained.

¹ H NMR (CD ₃ OD) δ 4.28-4.25 (1H, m), 3.67-3.58 (1H, m), 3.54-3.49 (1H, m), 3.40-3.32 (3H, m), 2.59-2.47 (2H , m), 2.37-2.30 (2H, m), 1.83-1.81 (4H, m), 1.44 (9H, s).

Mass (m / e) 301 (M + 1)

Production Example  44: 3- Trifluoromethyl -4,5,6,7- Tetrahydro - Ixoxazole [3,4- c ] Pyridine  synthesis

365 mg (1.24 mM) of tert-butyl 3-oxo-4- (trifluoroacetyl) -piperidine-1-carboxylate obtained with reference to WO 04/064778 were diluted in 7 ml of acetic acid, and then 107 mg (1.53 mM) of hydroxylamine was added thereto. It was refluxed. After refluxing for 6 hours, the reaction solution was cooled to room temperature, and acetic acid was removed under reduced pressure. Separation and purification using prep-TLC gave 45 mg (19%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 4.05 (1H, s), 3.04-3.02 (2H, m), 2.70-2.69 (2H, m)

Mass (m / e) 193 (M + 1)

Production Example  45: [3-oxo-1- (2-oxo-piperidin-1-ylmethyl) -3- (3-trifluoromethyl-4,5-di Heathrow -7 H -Isoxazolo [3,4- c ] Pyridin-6-yl) -propyl] -1S-carbamic acid t- Butyl Ester Synthesis of Le

20 mg (0.067 mM) of 3S-t-butoxycarbonylamino-4- (2-oxo-piperidin-1-yl) -butyric acid obtained in Preparation Example 42 was dissolved in 10 ml of dimethylformamide. 11.8 mg (0.087 mM) of 1-hydroxybenzotriazole and 166 mg (0.087 mM) of EDC were added sequentially at room temperature. After stirring for 10 minutes, 14 mg (0.073 mM) of 3-trifluoromethyl-4,5,6,7-tetrahydro-isoxazole [3,4, c ] pyridine obtained from Production Example 4 was diluted with dimethylformamide. It was dissolved in 3 ml and added slowly. After stirring for 10 minutes at room temperature, 0.035 ml (0.20 mM) of diisopropylethylamine was added. The mixture was stirred at room temperature for 12 hours, diluted with ethyl acetate, washed sequentially with 1N aqueous hydrochloric acid solution and brine, and the organic layer was filtered through anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by prep-TLC. 23 mg (73% yield) of the title compound were obtained.

¹ H NMR (CDCl ₃ ) δ 5.87-5.86 (1H, m), 4.86 (1H, brs), 4.76-4.70 (1H, m), 4.14 (1H, brs), 3.81 (1H, brs), 3.70-3.64 (2H, m), 3.44-3.30 (3H, m), 2.85-2.77 (2H, m), 2.50-2.45 (1H, m), 2.33-2.32 (2H, m), 1.83 (1H, brs), 1.77 -1.75 (4H, m), 1.39 (9H, s).

Mass (m / e) 475 (M + 1)

Production Example  46: [3-oxo-1- (2-oxo-piperidin-1-ylmethyl) -3- (3-trifluoromethyl-1,4,5,7-tetrahydro-pyrazolo [3, 4- c ] Pyridin-6-yl) -propyl] -1S-carbamic acid t- Butyl Synthesis of Ester

In the same manner as in Production Example 45, 17 mg (0.057 mM) of 3S-t-butoxycarbonylamino-4- (2-oxo-piperidin-1-yl) -butyric acid obtained from Preparation Example 43 and WO Title using 14 mg (0.062 mM) of 3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-pyrazolo [3,4- c ] pyridine hydrochloride obtained by reference to 04/064778 25 mg (93% yield) of compound were obtained.

¹ H NMR (CDCl ₃ ) δ 5.99-5.90 (1H, m), 4.82-4.64 (2H, m), 4.30-20 (1H, m), 3.90-3.84 (1H, m), 3.68-3.66 (1H, m), 3.64-3.31 (5H, m), 2.96-2.71 (3H, m), 2.66-2.56 (1H, m), 2.41-2.37 (2H, m), 1.93 (1H, brs), 1.79 (2H, brs), 1.39 (9H, m)

Mass (m / e) 474 (M + 1)

Example  19: 1- [2S-amino-4-oxo-4- (3-trifluoromethyl-4,5-dihydro-7H-isooxa Solo [3,4- c ] Pyridine Synthesis of -6-yl) butyl] -piperidin-2-one

In the same manner as in Example 3, [3-oxo-1- (2-oxo-piperidin-1-ylmethyl) -3- (3-trifluoromethyl-4,5-di obtained from Production Example 45) dihydro -7 H-iso-oxazolo [3,4- c] pyridin-6-yl) -propyl] -1S- carbamic acid t- butyl ester 23 mg (0.048 mM) from the title compound 9.9 mg (yield: 50% )

¹ H NMR (CD ₃ OD) δ 5.45-5.47 (1H, m), 3.86-3.68 (3H, m), 3.45-3.28 (4H, m), 2.90-2.68 (4H, m), 2.37-2.34 (2H , m), 1.89-1.78 (5H, m).

Mass (m / e) 375 (M + 1)

Example  20: 1- [2S-amino-4-oxo-4- (3-trifluoromethyl-1,4,5,7-tetrahydro-pi Lazolo [3,4- c ] Pyridine Synthesis of -6-yl) -butyl] -piperidin-2-one

In the same manner as in Example 3, [3-oxo-1- (2-oxo-piperidin-1-ylmethyl) -3- (3-trifluoromethyl-1,4,5) obtained from Production Example 46 8.9 mg (41% yield) of the title compound from 25 mg (0.053 mM) of 7-tetrahydro-pyrazolo [3,4- c ] pyridin-6-yl) -propyl] -1S-carbamic acid t-butylester )

¹ H NMR (CD ₃ OD) δ 4.84-4.73 (1H, m), 4.12-3.73 (3H, m), 3.54-3.37 (4H, m), 2.30-2.70 (4H, m), 2.46-2.34 (2H , m), 1.94-1.80 (5H, m).

Mass (m / e) 374 (M + 1)

Production Example  47: t-butyl 3-oxo-4- ( Trifluoroacetyl Piperidine-1- Carboxylate  synthesis

5.0 g (25 mM) of t-butyl 3-oxopiperidine-1-carboxylate was dissolved in dimethoxyethane, lowered to -78 ° C, and then lithium hexamethyldisilazide (LHMDS, 1M in THF) 30 ml (30 mmol) was added dropwise and stirred for about 1 hour, followed by dropwise addition of 3.9 ml (33 mM) of ethyltrifluoroacetate. After stirring for 1 hour, the dry ice / acetone bath was removed, and the mixture was stirred for about 2 hours and 30 minutes while the temperature was raised to room temperature. The reaction solution was washed with a saturated aqueous solution of ammonium chloride, extracted three times with ethyl acetate, and the obtained organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Methanol) to give 6.0 g (81%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 4.22 (2H, br s), 3.56 (2H, m), 2.57 (2H, br s), 1.49 (9H, s)

Mass (m / e) 296 (M + 1)

Production Example  48: 4- Trifluoromethyl -5,8- Dehydro -6 H -Pyrido [3,4-d] pyrimidine-7-carboxylic acid t- Butyl ester  synthesis

To 95 mg (1.18 mM) of formamidine hydrochloride dissolved in 2 ml of absolute ethanol, 0.52 ml of sodium ethoxide (21% wt. Ethanol solution) was added at room temperature. After stirring for 10 minutes, 232 mg (0.786 mM) of tert-butyl-3-oxo-4- (trifluoroacetyl) -piperidine-1-carboxylate (product of Preparation 47) obtained with reference to WO 04/064778 were dissolved in 2 ml of anhydrous ethanol. It was diluted with and added to the reaction solution. The reaction solution was warmed to 80 ° C. and stirred for 18 hours. After cooling to room temperature, ethanol was removed under reduced pressure, diluted with ethyl acetate and washed with brine. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting impure title compound was separated and purified using prep-TLC (ethyl acetate 20% normal hexane solvent) to obtain 30 mg (yield 13%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 9.11 (1H, s), 4.73 (2H, s), 3.72 (2H, t, J = 5.5 Hz), 3.02 (2H, br s), 1.48 (9H, s)

Mass (m / e) 248 (M + 1-t-butyl)

Production Example  49: 4- Trifluoromethyl -5,6,7,8- Tetrahydropyrido [3,4-d] pyrimidine  Synthesis of Hydrochloride

3-N hydrochloric acid in 30 mg (0.099 mM) of 4-trifluoromethyl-5,8-dihydro-6H-pyrido [3,4-d] pyrimidine-7-carboxylic acid t-butyl ester obtained from Preparation Example 48. 1.8 ml of ethyl acetate solution was added at room temperature. After stirring for 10 minutes at room temperature, excess hydrochloric acid-ethyl acetate solution was removed and concentrated. The title compound obtained was used for the next reaction without further purification.

¹ H NMR (CD ₃ OD) δ 4.44 (2H, s), 3.55-3.52 (2H, m), 3.23-3.20 (2H, m)

Mass (m / e) 204 (M + 1)

Production Example  50: (3S) -t- Butoxycarbonylamino -4-[(5R- methyl -2-oxo-piperidin-1-yl)]- part Tanoic acid t- Butyl ester  synthesis

In the same manner as in Preparation Example 42, 363 mg (1.33 mM) of 3S-t-butoxycarbonylamino-4-oxo-butyric acid t-butylester (product of Preparation Example 41) and (R) obtained from Preparation Example 7 220 mg (1.21 mM) of) -5-amino-4-methyl-pentanoic acid methyl ester hydrochloride was used to obtain 359 mg (yield 73%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 5.40-5.31 (1H, m), 4.17 (1H, br s), 3.89-3.80 (1H, m), 3.25-3.03 (3H, m), 2.58-2.29 (2H, m ), 1.98-1.88 (1H, m), 1.84-1.80 (1H, m), 1.46 (9H, s), 1.42 (9H, s), 1.01 (3H, d, J = 6.4 Hz)

Mass (m / e) 371 (M + 1)

Production Example  51: (3S) -3-[(t- Butoxycarbonyl ) Amino] -4- (5R- methyl 2-oxo-piperidin-1-yl)- Butanoic  synthesis

In the same manner as in Production Example 43, (3S) -t-butoxycarbonylamino-4-[(5R) -methyl-2-oxo-piperidin-1-yl] -butyric acid obtained from Production Example 50 116 mg (yield 38%) of the title compound were obtained using 359 mg (0.97 mM) of t-butyl ester.

¹ H NMR (CDCl ₃ ) δ 8.50 (1H, br s), 5.75-5.73 (1H, m), 4.16 (1H, br s), 3.76-3.54 (2H, m), 3.44-3.34 (1H, m) , 3.16-2.97 (1H, m), 2.59-2.38 (4H, m), 1.98 (1H, br s), 1.86-1.84 (1H, m), 1.45 (9H, s), 1.04 (3H, d, J = 6.8 Hz)

Mass (m / e) 315 (M + 1)

Production Example  52: [1- (5R-Methyl-2-oxo-piperidin-1-ylmethyl) -3-oxo-3- (4-trifluoromethyl-5,8-dihydro-6 H - Pyrido [3,4-d] pyrimidine -7-yl) -propyl] -1S- Carbamic acid  t- Butyl S Synthesis of Ter

In the same manner as in Production Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(5R) -methyl-2-oxo-piperidine-1- obtained from Production Example 51 26 mg of 4-trifluoromethyl-5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine hydrochloride obtained from 34.1 mg (0.108 mM) of mono] -butyric acid and 0.109 mM) to give 35 mg (yield 65%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 9.15 (1H, s), 5.95-5.88 (1H, m), 4.95-4.70 (2H, m), 4.15 (1H, br s), 3.92-3.89 (1H, m), 3.86-3.80 (1H, m), 3.57-3.55 (1H, m), 3.36 (1H, br s), 3.09-3.00 (3H, m), 2.89-2.81 (1H, m), 2.54-2.30 (3H, m), 1.94 (1H, br s), 1.81 (1H, br s), 1.64 (2H, br s), 1.42-1.40 (9H, m), 1.02-1.00 (3H, m)

Mass (m / e) 500 (M + 1)

Example 21 1- [2S-amino-4-oxo-4- (4-trifluoromethyl-5,8-dihydro-6 H -pyrido [3,4-d] pyrimidin- 7 - yl Synthesis of) -Butyl] -5R- methyl -1-piperidin-2-one

In the same manner as in Example 3, 1- (5R-methyl-2-oxo-piperidin-1-ylmethyl) -3-oxo-3- (4-trifluoromethyl-5, obtained from Preparation Example 52, 14.5 mg of the title compound from 35 mg (0.053 mM) of 8-dihydro-6 H -pyrido [3,4-d] pyrimidin-7-yl) -propyl] -1S-carbamic acid t-butylester (Yield 51%) was obtained.

¹ H NMR (CD ₃ OD) δ 9.15-9.14 (1H, m), 9.95 (1H, t, J = 6.0 Hz), 3.90-3.86 (1H, m), 3.80-3.77 (1H, m), 3.71- 3.65 (1H, m), 3.58-3.53 (1H, m), 3.48-3.37 (3H, m), 3.18-3.07 (3H, m), 2.94-2.87 (1H, m), 2.80-2.75 (1H, m ), 2.58-2.34 (2H, m), 2.05-2.03 (1H, m), 1.89-1.85 (1H, m), 1.60-1.47 (1H, m), 1.06 (3H, d, J = 2.8 Hz)

Mass (m / e) 374 (M + 1)

Production Example  53: (S)-(2-amino-1- methyl - Ethoxy )- Acetic acid  Synthesis of Ethyl Ester Hydrochloride

(One) (S)-(2-hydroxy-propyl)- Carbamic acid  Synthesis of t-butyl ester

Dissolve (S) -1-amino-propan-2-ol (500 mg, 6.65 mM) in 20 ml of methanol and 5 ml of water, add di-t-butyl dicarbonate (1.85 g, 8.45 mM) for 3 hours. Stirred at room temperature. 200 ml of ethyl acetate was added to the reaction, washed with water, and the organic layer was dried over magnesium sulfate. After distillation of the solvent under reduced pressure, 802 g (4.57 mM) of the title compound were obtained by column chromatography in 68% yield.

NMR: ¹ H-NMR (CDCl ₃ ) δ 4.91 (1H, brs), 3.95-3.85 (1H, m), 3.30-3.22 (1H, m), 3.04--2.97 (1H, m), 2.31 (1H, brs ), 1.45 (9H, s), 1.18 (3H, d, J = 8 Hz)

Mass (EI) 176 (M ⁺ +1)

(2) (S)-(2-t- Butoxycarbonylamino -One- methyl - Ethoxy )- Acetic acid  Synthesis of Ethyl Ester

(S)-(2-hydroxy-propyl) -carbamic acid t-butyl ester (1.16 g, 6.61 mM) was dissolved in 20 ml of dichloroethane, and then 0.66 ml (9.84 mM) of ethyl diazoacetate was added thereto. . Rhodium acetate (57 mg, 0.12 mM) was added dropwise to the reaction solution, followed by heating at 80 ° C. for 2 hours. After distillation of the solvent under reduced pressure, 1.2 g (4.59 mM) of the title compound were obtained in 69% yield by column chromatography.

NMR: ¹ H-NMR (CDCl ₃ ) δ 5.39 (1H, s), 4.23 (2H, q, J = 8 Hz), 4.09 (1H, d, J = 16 Hz), 4.00 (1H, d, J = 16 Hz) , 3.60-3.35 (1H, m), 3.35-3.15 (1H, m), 3.10-3.04 (1H, m), 1.46 (9H, s), 1.31 (3H, t, J = 4 Hz), 1.16 (3H, d, J = 4 Hz)

Mass (EI) 262 (M ⁺ +1)

(3) (S)-(2-amino-1- methyl - Ethoxy )- Acetic acid  Synthesis of Ethyl Ester Hydrochloride

(S)-(2-t-butoxycarbonylamino-1-methyl-ethoxy) -acetic acid ethyl ester (1.2 g, 4.59 mM) was dissolved in 20 ml of ethyl acetate saturated with hydrochloric acid gas, and then dried at room temperature. Stirred for time. After distillation of the solvent under reduced pressure, 699 mg (3.49 mM) of the title compound were obtained by column chromatography in 76% yield.

NMR: ¹ H-NMR (CD ₃ OD) δ 5.05 (2H, s), 4.32-4.19 (4H, m), 3.88-3.83 (1H, m), 3.16-3.12 (1H, m), 2.96-2.90 ( 1H, m), 1.32 (3H, t, J = 7.2 Hz), 1.25 (3H, d, J = 6 Hz)

Mass (EI) 200 (M ⁺ +1)

Production Example  54: t-butyl  (3S) -3-[(t-butoxycarbonyl) amino] -4-[(2S) -2-methyl-5-oxomorpholin-4-yl]- Butanoate  synthesis

(S) -2-amino-1-methylethoxy) obtained from Production Example 53 of 3S-t-butoxycarbonylamino-4-oxo-butyric acid t-butylester obtained in the same manner as in Production Example 41) 457 mg (2.31 mM) of acetate hydrochloride were reacted in the same manner as in Preparation 50 to obtain 767 mg (two steps yield 81%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 5.22 (1H, d, J = 8.5 Hz), 4.17 (2H, Abq, J = 18 Hz), 3.87 (1H, m), 3.66 (1H, dd, J = 13.5, 8.5 Hz), 3.41 (1H, t, J = 11.0 Hz), 3.31 (1H, dd, J = 13.5 5.0 Hz), 2.90 (1H, dd, J = 12.0, 2.5 Hz), 2.52 (1H, dd, J = 16.0, 5.0 Hz), 2.41 (1H, dd, J = 16.0, 6,5 Hz), 1.44 (9H, s), 1.41 (9H, s), 1.25 (3H, d, J = 6.0 Hz)

Mass (m / e) 395 (M + Na)

Production Example  55: Synthesis of (3S) -3-[(t-butoxycarbonyl) amino] -4-[(2S) -2-methyl-5-oxomorpholin-4-yl] -butanoic acid

T-butyl (3S) -3-[(t-butoxycarbonyl) amino] -4-[(2S) -2-methyl-5-oxomorpholin-4-yl] -butano obtained from Preparation Example 54 580 mg (two steps yield 89%) of the title compound were obtained in the same manner as in Preparation Example 43 using 767 mg (2.06 mM) of Eate.

¹ H NMR (CD ₃ OD) δ 4.23 (1H, m), 4.11 (2H, s), 3.88 (1H, m), 3.50 (1H, dd, J = 13.5 8.5 Hz), 3.39 (2H, m), 2.50 (1H, dd, J = 16, 6 Hz), 2.44 (1H, dd, J = 16, 7 Hz), 1.41 (9H, s), 1.22 (3H, d, J = 7 Hz)

Mass (m / e) 317 (M + 1)

Production Example  56: t-butyl  (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidin-1-yl)- Butanoate  synthesis

5-Amino-4,4-difluoro obtained from 3S-t-butoxycarbonylamino-4-oxo-butyric acid t-butylester (Preparation Example 41) and Preparation Example 12 in the same manner as in Preparation Example 42 471 mg (2.31 mM) of lofentanoate hydrochloride were used to obtain 900 mg (yield 90%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 5.19 (1H, d, J = 8.0 Hz), 3.5-4.0 (4H, m), 3.20 (1H, dd, J = 14, 4 Hz), 2.6 (2H, m), 2.5 (1H, dd, J = 16, 4 Hz), 2.4 (1H, dd, J = 16, 8 Hz), 2.2-2.3 (2H, m), 1.46 (9H, s), 1.42 (9H, s)

Mass (m / e) 393 (M + 1)

Production Example  57: (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidin-1-yl)- Butanoic  synthesis

T-butyl (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperi obtained from Preparation Example 56 in the same manner as in Preparation Example 43 900 mg (2.29 mM) of din-1-yl) -butanoate were used to give 298 mg (two steps yield 39%) of the title compound.

¹ H NMR (CD ₃ OD) δ 4.19 (1H, m), 3.87 (1H, br q, J = 13 Hz), 3.7 (1H, br q, J = 13 Hz), 3.52 (1H, dd, J = 14, 9 Hz), 3.37 (1H, m), 2.4-2.6 (4H, m), 2.2-2.3 (2H, m), 1.40 (9H, s)

Mass (m / e) 337 (M + 1)

Production Example  58: 2- (4- Fluorophenyl )-4-( Trifluoromethyl ) -5,6,7,8- Tetrahydropyrido [3,4- d ] Pyrimidine  Synthesis of Hydrochloride

(One) 4- Of fluorobenzenecarboxymidamide  synthesis

Trimethyl aluminum (4.12 ml, 8.24 mM, 2.0 M toluene solution) is added dropwise to 10 ml of toluene with ammonium chloride (441 mg, 8.24 mM) at room temperature. After stirring for 1 hour 30 minutes, 4-fluorobenzonitrile (1 g, 8.25 mM) was added thereto and heated at 85 ° C. for 9 hours. After the reaction, the solution was cooled, poured into 100 ml of chloroform containing 200 g of silica gel, filtered, washed with 100 ml of methanol, and distilled to obtain 821 mg (5.9 mM) of the compound in 71% yield.

NMR: ¹ H-NMR (DMSO d6) δ 9.44 (1H, brs), 9.25 (1H, brs), 7.96-7.72 (2H, m), 7.52-7.31 (2H, m)

Mass (EI) 139 (M ⁺ +1)

(2) t-butyl 2 -(4- Fluorophenyl )-4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4- d ] Pyrimidine-7 (6 H )- Carboxylate  synthesis

500 mg (1.69 mM) of t-butyl 3-oxo-4- (trifluoroacetyl) piperidine-1-carboxylate obtained in Preparation Example 47 and 4-fluorobenzenecarboxymida obtained in step (1). Meade 351 m (2.54 mM) was reacted to give 108 mg (16% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 8.47 (2H, m), 7.16 (2H, t, J = 8.5 Hz), 4.76 (2H, s), 3.74 (2H, t, J = 6.0 Hz), 3.02 (2H, br s), 1.51 (9H, s)

Mass (m / e) 398 (M + 1)

(3) 2- (4- Fluorophenyl )-4-( Trifluoromethyl ) -5,6,7,8- Tetrahydropyrido [3,4-  d ] Synthesis of pyrimidine hydrochloride

T-butyl 2- (4-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 (6) obtained in step (2) above. H ) -carboxylate To 108 mg (0.306 mM) 7.5 ml of a 4 N hydrochloric acid / 1,4-dioxane solution was added at room temperature. After stirring for 25 minutes at room temperature, excess hydrochloric acid / 1,4-dioxane solution was removed and concentrated. 69 mg (yield 85%) of the title compound obtained were used for the next reaction without further purification.

¹ H NMR (CD ₃ OD) δ 8.54 (2H, m), 7.29 (2H, t, J = 10.0 Hz), 4.60 (2H, s), 3.67 (2H, t, J = 6.0 Hz), remaining 2 It is assumed that protons are buried at 3.3 ppm of CD ₃ OD.

Mass (m / e) 298 (M + 1)

Production Example  59: 2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyripy Degree [3,4-d] pyrimidine  Synthesis of Hydrochloride

(One) 3,4- Of difluorobenzenecarboxymidamide  synthesis

Trimethyl aluminum (3.6 ml, 7.2 mM, 2.0 M toluene solution) was added dropwise to 10 ml of toluene with ammonium chloride (384 mg, 7.17 mM) at room temperature, then stirred for 1 hour 30 minutes and then 3,4-difluoro Robenzonitrile (1 g, 7.1 mM) was added. Then, after heating at 85 ° C. for 9 hours, the solution was cooled, poured into 100 ml of chloroform containing 200 g of silica gel, filtered, washed with 100 ml of methanol, and then distilled to obtain 370 mg (2.36 mM) of the compound. Obtained in 33% yield.

NMR: ¹ H-NMR (CD ₃ OD) δ 7.87-7.82 (1H, m), 7.72-7.70 (1H, m), 7.63-7.55 (1H, m)

Mass (EI) 157 (M ⁺ +1)

(2) t- butyl 2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin -7 (6 H ) synthesis of carboxylate

In the same manner as in Preparation Example 58 (2), 380 mg (1.28 mM) of t-butyl 3-oxo-4- (trifluoroacetyl) piperidine-1-carboxylate obtained in Preparation Example 47 and the step ( 25 mg (yield 4.7%) of the title compound were obtained using 300 mg (1.92 mM) of 3,4-difluorobenzenecarboxymidamide obtained in 1).

¹ H NMR (CDCl ₃ ) δ 8.3 (2H, m), 7.25 (1H, m), 4.76 (2H, s), 3.75 (2H, t, J = 6.0 Hz), 3.03 (2H, br s), 1.51 (9H, s)

Mass (m / e) 416 (M + 1)

(3) 2- (3,4- Difluorophenyl )-4-( Trifluoromethyl ) -5,6,7,8- Tetrahydropyri Degree[ 3,4- d ] Pyrimidine  Synthesis of Hydrochloride

In the same manner as in Preparation Example 59 (3), t-butyl 2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5,8-dihydropyri obtained from step (2) 14 mg (yield 74%) of the title compound were obtained using 25 mg (0.62 mM) of FIG. 3,4- d ] pyrimidine-7 ( 6H ) -carboxylate.

¹ H NMR (CD ₃ OD) δ 8.36 (2H, m), 7.48 (1H, m), 4.60 (2H, s), 3.66 (2H, t, J = 7.5 Hz), 3.12 (2H, m)

Mass (m / e) 316 (M + 1)

Preparation Example 60 Synthesis of 2- (3-fluorophenyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine hydrochloride

(One) 3- Of fluorobenzenecarboxymidamide  synthesis

Trimethyl aluminum (4.12 ml, 8.24 mM, 2.0 M toluene solution) was added dropwise to 10 ml of toluene with ammonium chloride (441 mg, 8.24 mM) at room temperature, followed by stirring for 1 hour 30 minutes and then 3-fluorobenzonitrile ( 1 g, 8.25 mM) was heated at 85 ° C. for 9 hours. After the reaction, the solution was cooled, poured into 100 ml of chloroform containing 200 g of silica gel, filtered, washed with 100 ml of methanol and distilled to obtain 731 mg (5.29 mM) of the compound in 64% yield.

NMR: ¹ H-NMR (CD ₃ OD) δ 7.71-7.44 (4H, m)

Mass (EI) 139 (M ⁺ +1)

(2) t-butyl 2 -(3- Fluorophenyl )-4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4- d] pyrimidine-7 (6 H )- Carboxylate  synthesis

In the same manner as in Production Example 61-58 (2), 600 mg (2.03 mM) of t-butyl 3-oxo-4- (trifluoroacetyl) piperidine-1-carboxylate obtained in Production Example 47 and the 421 mg (3.05 mM) of 3-fluorobenzenecarboxymidamide obtained in step (1) were used to obtain 159 mg (yield 20%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 8.25 (1H, d, J = 8.0 Hz), 8.15 (1H, m), 7.45 (1H, m), 7.18 (1H, m), 4.78 (2H, s), 3.75 ( 2H, t, J = 6.0 Hz), 3.13 (2H, br s), 1.52 (9H, s)

Mass (m / e) 398 (M + 1)

(3) 2- (3- Fluorophenyl )-4-( Trifluoromethyl ) -5,6,7,8- Tetrahydropyrido [3,4- d ] Synthesis of Pyrimidine Hydrochloride

In the same manner as in Production Example 58 (3), t-butyl 2- (3-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3] was obtained from step (2). 88 mg (yield 67%) of the title compound were obtained using 159 mg (0.62 mM) of, 4- d ] pyrimidine-7 ( 6H ) -carboxylate.

¹ H NMR (CD ₃ OD) δ 8.33 (1H, m), 8.17 (1H, m), 7.58 (1H, m), 7.34 (1H, m), 4.62 (2H, s), 3.67 (2H, t, J = 6.5 Hz), 3.35 (2H, m)

Mass (m / e) 298 (M + 1)

Production Example  61: 2- Cyclopropyl -4-( Trifluoromethyl ) -5,6,7,8- Tetrahydropyrido [3,4- d ] Pyrimidine  Synthesis of Hydrochloride

(One) t-butyl  2- Cyclopropyl -4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4- d ]blood Limidine-7 (6 H )- Carboxylate  synthesis

1.500 g of sodium ethoxide (21% wt. Ethanol solution) was added at room temperature with 500 mg (4.13 mM) of cyclopropanecarboxymidamide hydrochloride dissolved in 50 ml of isopropanol. After stirring for 30 minutes, concentrated and filtered, 940 mg (3.17 mM) of t-butyl 3-oxo-4- (trifluoroacetyl) piperidine-1-carboxylate obtained in Preparation 47 was added thereto. 12 μl (3% catalytic amount) of borontrifluoride diethyl acrylate (BF ₃ OEt ₂ ) was added thereto, and the reaction solution was then heated to 80 ° C. and stirred for 19 hours. Then, after cooling to room temperature, the impure title compound obtained by removing isopropanol under reduced pressure was purified by column chromatography (10: 1 hexane: ethyl acetate) to give 400 mg (yield 37%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 4.62 (2H, s), 3.68 (2H, t, J = 5.5 Hz), 2.93 (2H, br s), 2.25 (1H, m), 1.49 (9H, s), 1.1 -1.2 (4H, m)

Mass (m / e) 344 (M + 1)

(2) 2- Cyclopropyl -4-( Trifluoromethyl ) -5,6,7,8- Tetrahydropyrido [3,4-d] pi Synthesis of Limidine Hydrochloride

T-butyl 2-cyclopropyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] obtained from the step (1) in the same manner as in Production Example 58 (3). 400 mg (1.16 mM) of pyrimidine-7 ( 6H ) -carboxylate gave 264 mg (yield 81%) of the title compound.

¹ H NMR (CD ₃ OD) δ 4.40 (2H, s), 3.56 (2H, t, J = 6.5 Hz), 3.20 (2H, t, J = 6.5 Hz), 2.29 (1H, m), 1.20 (4H , m)

Mass (m / e) 244 (M + 1)

Production Example  62: 2- Cyclopentyl -4-( Trifluoromethyl ) -5,6,7,8- Tetrahydropyrido [3,4- d ] Pyrimidine  Synthesis of Hydrochloride

(One) t-butyl  2- Cyclopentyl -4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4- d ]Pipe Midine-7 (6 H )- Carboxylate  synthesis

Pyridine (10 ml) was dissolved in 1.0 g (3.39 mM) of t-butyl 3-oxo-4- (trifluoroacetyl) piperidine-1-carboxylate obtained in Production Example 47, and then dissolved in cyclopentanecarboxymida. 380 mg (3.39 mM) of dihydrochloride hydrochloride was added, and the reaction solution was warmed to about 120 ° C. and stirred for 1 hour and 20 minutes. Then, after cooling to room temperature, pyridine was removed under reduced pressure, and the resulting impure title compound was purified by column chromatography (10: 1 hexane: ethyl acetate) to give 688 mg (yield 55%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 4.67 (2H, s), 3.70 (2H, t, J = 5.5 Hz), 3.34 (1H, m), 2.96 (2H, br s), 2.07 (2H, m), 1.8 -2.0 (4H, m), 1.70 (2H, m), 1.49 (9H, s)

Mass (m / e) 372 (M + 1)

(2) 2- Cyclopentyl -4-( Trifluoromethyl ) -5,6,7,8- Tetrahydropyrido [3,4- d ]Pipe Synthesis of Midine Hydrochloride

T-butyl 2-cyclopentyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] obtained in the same manner as in Production Example 58 (3), from step (1). 688 mg (1.85 mM) of pyrimidine-7 (6 H ) -carboxylate were used to give 480 mg (yield 84%) of the title compound.

¹ H NMR (CD ₃ OD) δ 4.44 (2H, s), 3.58 (2H, t, J = 6.5 Hz), 3.4 (1H, m), 3.20 (2H, t, J = 6.5 Hz), 2.07 (2H , m), 1.8-2.0 (4H, m), 1.70 (2H, m)

Mass (m / e) 272 (M + 1)

Production Example  63: 2-phenyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- d ] Pyrami Dean  Synthesis of Hydrochloride

(One) t-butyl  2- Phenyl -4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4- d ] Pyrimidine -7 (6 H ) -Ka Leboxile Synthesis of sites

In the same manner as in Production Example 61 (1), 1.0 g (3.39 mM) of t-butyl 3-oxo-4- (trifluoroacetyl) piperidine-1-carboxylate obtained in Production Example 47 and benzenecarboxy 530 mg (3.39 mM) of midamide hydrochloride were used to obtain 900 mg (yield 70%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 8.46 (2H, m), 7.49 (3H, m), 4.78 (2H, s), 3.75 (2H, t, J = 5.5 Hz), 3.03 (2H, br s), 1.51 (9H, s)

Mass (m / e) 380 (M + 1)

(2) 2- Phenyl -4-( Trifluoromethyl ) -5,6,7,8- Tetrahydropyrido [3,4- d ] Pyrimidine  Synthesis of Hydrochloride

T-butyl 2-phenyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrile obtained in the same manner as in Production Example 58 (3), from step (1). 900 mg (2.37 mM) of midine-7 ( 6H ) -carboxylate were used to give 730 mg (yield 97%) of the title compound.

¹ H NMR (CD ₃ OD) δ 8.50 (2H, m), 7.57 (3H, m), 4.61 (2H, s), 3.67 (2H, t, J = 7.5 Hz), 3.30 (2H, m)

Mass (m / e) 280 (M + 1)

Production Example  72: t-butyl  {(1S) -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxo-3- [2- Phenyl -4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -General] profile Carbamate  synthesis

77 mg (0.24 mM) of 3S-t-butoxycarbonylamino-4- (5R-methyl-2-oxo-piperidin-1-yl) -butyric acid obtained from Preparation Example 51 and Preparation Example 63 70 mg (0.22 mM) of 2-phenyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine hydrochloride are dissolved in 5 ml of methylene chloride and 1- 36 mg (0.27 mM) of hydroxybenzotriazole and 64 mg (0.33 mM) of EDC were added sequentially at room temperature. Then, after stirring for 10 minutes at room temperature, 0.12 ml (0.67 mM) of N, N-diisopropylethylamine was added. After stirring for 5 hours at room temperature, diluted with ethyl acetate, washed successively with 1 N aqueous hydrochloric acid solution and brine, and dried the organic layer with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. 120 mg (94% yield) of compound were obtained.

¹ H NMR (CDCl ₃ ) δ 8.46 (2H, m), 7.50 (3H, m), 5.86 (1H, m), 4.93 (1H, s), 4.8 (1H, ABq, J = 16 Hz), 4.2 ( 1H, m), 3.92 (1H, m), 3.8 (1H, m), 3.63 (1H, m), 3.36 (1H, m), 3.0-3.2 (3H, m), 2.88 (1H, m), 2.3 -2.6 (3H, m), 1.8-2.0 (2H, m), 1.40 (9H, m), 1.00 (3H, d, J = 6.5 Hz)

Mass (m / e) 576 (M + 1)

Example  22: (5R) -1-{(2S) -2-amino-4-oxo-4- [2-phenyl-4- (trifluoromethyl) -5,8-dihydropyrido [ 3,4-d] pyrimidine -7 (6H) -yl] butyl} -5- Methylpiperidine Synthesis of 2-one

T-butyl {(1S) -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxo-3- [2-phenyl- obtained from Production Example 64 4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] propyl} carbamate 120 mg (0.21 mM) in 1,4- It was dissolved in dioxane / hydrochloric acid, then stirred for about 30 minutes, concentrated, and the residue was purified by prep-TLC (10: 1 CH ₂ Cl ₂ : MeOH) to give 83 mg (yield 84) of the title compound. %) Was obtained.

¹ H NMR (CD ₃ OD) δ 8.46 (2H, m), 7.50 (3H, m), 5.0-4.8 (2H, m), 3.94 (1H, t, J = 6.5 Hz), 3.86 (1H, m) , 3.75 (1H, m), 3.64 (1H, m), 3.53 (1H, m), 3.3-3.4 (1H, m), 3.0-3.2 (3H, m), 2.86 (1H, m), 2.70 (1H , m), 2.3-2.5 (2H, m), 2.0 (1H, m), 1.84 (1H, m), 1.52 (1H, m), 1.02 (3H, m)

Mass (m / e) 476 (M + 1)

Production Example  65: t-butyl [(1S) -1-{[(2S) -2-methyl-5-oxomorpholin-4-yl] methyl} 3-oxo-3- [2-phenyl-4- ( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine Synthesis of -7 (6H) -yl] propyl] carbamate

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(2S) -2-methyl-5-oxomorpholin-4- obtained from Preparation Example 55 77 mg (0.24 mM) of 1] -butanoic acid and 2-phenyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d] obtained from Preparation Example 63 70 mg (0.22 mM) of pyrimidine hydrochloride were reacted to give 182 mg of the title compound (yield 99%).

¹ H NMR (CDCl ₃ ) δ 8.46 (2H, m), 7.51 (3H, m), 5.80 (1H, m), 4.93 (1H, s), 4.8 (1H, ABq, J = 16 Hz), 4.2- 4.3 (2H, m), 3.8-4.0 (3H, m), 3.6-3.7 (1H, m), 3.5-3.6 (1H, m), 3.3-3.4 (2H, m), 3.0-3.2 (2H, m ), 2.8-2.9 (1H, m), 2.5-2.6 (1H, m), 1.41 (9H, m), 1.26 (3H, d, J = 6.5 Hz)

Mass (m / e) 578 (M + 1)

Example  23: (6S) -4-{(2S) -2-amino-4-oxo-4- [2-phenyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d] Synthesis of pyrimidin-7 (6H) -yl] butyl} -6-methylmorpholin-3-one.

T-butyl [(1S) -1-{[(2S) -2-methyl-5-oxomorpholin-4-yl] methyl} 3-oxo-3 obtained in the same manner as in Example 23; -[2-phenyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] propyl] carbamate 91 mg (87% yield) of the title compound were obtained from 127 mg (0.22 mM).

¹ H NMR (CD ₃ OD) δ 8.46 (2H, m), 7.50 (3H, m), 5.0-4.8 (2H, m), 4.0-4.2 (2H, m), 3.8-4.0 (3H, m), 3.7-3.8 (1H, m), 3.5-3.6 (2H, m), 3.53 (1H, m), 3.3-3.4 (2H, m), 3.0-3.2 (2H, m), 2.8-2.9 (1H, m ), 2.6-2.7 (1H, m), 1.23 (3H, m)

Mass (m / e) 478 (M + 1)

Production Example  66: t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] 3-oxo-3- [2- Phenyl -4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] propyl} Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidine-1 obtained from Preparation Example 57 -Yl) -butanoic acid 82 mg (0.24 mM) and 2-phenyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d obtained from Preparation Example 71 ] 70 mg (0.22 mM) of pyrimidine hydrochloride gave 108 mg (yield 82%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 8.46 (2H, m), 7.50 (3H, m), 5.78 (1H, m), 4.93 (1H, s), 4.78 (1H, ABq, J = 16 Hz), 4.22 ( 1H, m), 3.92 (1H, m), 3.7-3.8 (3H, m), 3.5-3.7 (2H, m), 3.0-3.2 (2H, m), 2.84 (1H, m), 2.56 (3H, m), 2.27 (2H, m), 1.41 (9H, m)

Mass (m / e) 598 (M + 1)

Example  24: 1-{(2S) -2-amino-4-oxo-4- [2-phenyl-4- (trifluoromethyl) -5,8-dihydrate Ropyrido [3,4-d] pyrimidine Synthesis of -7 (6H) -yl] butyl} -5,5-difluoropiperidin-2-one

T-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] 3-oxo- obtained from Production Example 65 in the same manner as in Example 23 108 mg (0.18) of 3- [2-phenyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] propyl} carbamate mM) gave 78 mg (87% yield) of the title compound.

¹ H NMR (CD ₃ OD) δ 8.46 (2H, m), 7.50 (3H, m), 5.0-4.8 (2H, m), 3.6-4.0 (6H, m), 3.48 (1H, m), 3.0- 3.2 (2H, m), 2.83 (1H, m), 2.71 (1H, m), 2.57 (2H, m), 2.34 (2H, m)

Mass (m / e) 498 (M + 1)

Production Example  67: t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3- [2-hour Clopropyl -4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -3-jade Sopro Phil} Carbamate  synthesis

(3S) -3-[(t-butoxycarboxyl) amino] -4- (5,5-difluoro-2-oxopiperidin-1-yl) butanoic acid (8.4) obtained from Production Example 57. mg, 0.024 mM) 2-cyclopropyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine hydrochloride (7 mg) obtained from Preparation Example 61 , 0.025 mM) to give 12 mg (0.021 mM) of the title compound in 87% yield using the experimental method of Preparation Example 45.

Mass (EI) 562 (M ⁺ +1)

Example  25: 1-{(2S) -2-amino-4- [2-cyclopropyl-4- (trifluoromethyl) -5,8-dihydrate Ropyrido [3,4-d] pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one hydrochloride

T-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3- [2-cyclopropyl-4- (obtained from Preparation Example 67 Example from trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] -3-oxopropyl} carbamate (12 mg, 0.021 mM) Using the experimental method of 23, 6 mg (0.012 mM) of the title compound were obtained in 57% yield.

NMR: ¹ H-NMR (CD ₃ OD) δ 4.84 to 4.73 (2H, m), 3.89 to 3.76 (4H, m), 3.55 to 3.47 (3H, m), 3.10 to 2.96 (2H, m), 2.69 to 2.55 (4H, m), 2.39-2.17 (3H, m), 1.17-1.92 (4H, m)

Mass (EI) 462 (M ⁺ +1)

Production Example  68: t-butyl (1S) -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl) methyl] -3- [2-cyclo profile -4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -3-oxopropyl} Carbamate  synthesis

(3S) -3-[(t-butoxycarboxyl) amino] -4-[(5R) -5-methyl-2-oxopiperidin-1-yl] butanoic acid (8.0 obtained from Preparation Example 51) mg, 0.025 mM) 2-cyclopropyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine hydrochloride (7 mg) obtained from Preparation Example 61 , 0.025 mM) to give the title compound 11 mg (0.020 mM) in 80% yield using the experimental method of Preparation 45.

Mass (EI) 540 (M ⁺ +1)

Example  26: 1-{(2S) -2-amino-4- [2-cyclopropyl-4- (trifluoromethyl) -5,8-dihydrate Ropyrido [3,4-d] pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one hydrochloride

T-butyl (1S) -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3- [2-cyclopropyl-4- (tri) obtained from Preparation Example 68 Example 23 from fluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] -3-oxopropyl} carbamate (11 mg, 0.020 mM) Using the experimental method of 7 mg (0.014 mM) of the title compound was obtained in 70% yield.

NMR: ¹ H-NMR (CD ₃ OD) δ 4.80 to 4.73 (2H, m), 3.89 to 3.81 (2H, m), 3.70 to 3.60 (1H, m), 3.52 to 3.50 (2H, m), 3.40 to 3.37 (1H, m), 3.10-2.90 (3H, m), 2.77-2.72 (1H, m), 2.65-2.59 (1H, m), 2.42-2.17 (3H, m), 2.10-1.95 (1H, m) ), 1.90-1.80 (1H, m), 1.58-1.49 (1H, m), 1.13 (3H, d, J = 6.4 Hz), 1.04 (4H, d, J = 6.4 Hz)

Mass (EI) 440 (M ⁺ +1)

Production Example  69: t-butyl (1S) -1-{[(2R) -2-methyl-5-oxomorpholin-4-yl) methyl] -3- [2-cyclopropyl-4- ( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -3- Oxo profile} Carbamate  synthesis

(3S) -3-[(t-butoxycarboxyl) amino] -4-[(2S) -2-methyl-5-oxopiperidinemorpholin-4-yl] butanoic acid obtained from Production Example 55 ( 8.0 mg, 0.025 mM) 2-cyclopropyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine hydrochloride obtained from Preparation Example 61 (7 mg, 0.025 mM) to give 12 mg (0.022 mM) of the title compound in 88% yield using the experimental method of Preparation Example 45.

Mass (EI) 528 (M ⁺ +1)

Example  27: (6S) -4-{(2S) -2-amino-4- [2-cyclopropyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrid Synthesis of midin-7 (6H) -yl] -4-oxobutyl} -6-methylmorpholin-3-one hydrochloride

T-butyl (1S) -1-{[(2R) -2-methyl-5-oxomorpholin-4-yl] methyl} -3- [2-cyclopropyl-4- (trifluoro) obtained from Production Example 69 Rommethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] -3-oxopropyl} carbamate (12 mg, 0.022 mM) Using the experimental method, 7 mg (0.014 mM) of the title compound were obtained in 63% yield.

NMR: ¹ H-NMR (CD ₃ OD) δ 4.80-4.73 (2H, m), 4.20-4.13 (2H, m), 3.97-3.82 (3H, m), 3.60-3.52 (2H, m), 3.46- 3.32 (3H, m), 3.10-3.05 (1H, m), 3.00-2.94 (1H, m), 2.73-2.68 (1H, m), 2.62-2.56 (1H, m), 2.30-2.17 (1H, m) ), 1.25 (3H, d, J = 6.0 Hz), 1.15 (4H, d, J = 9.2 Hz)

Mass (EI) 442 (M ⁺ +1)

Production Example  70: t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3-oxo-3- [5- (t Lifluor Rhomethyl) -3,4- Dehydroisocunoline -2 (1H) -yl] propyl} Carbamate  synthesis

(3S) -3-[(t-butoxycarboxyl) amino] -4- (5,5-difluoro-2-oxopiperidin-1-yl) butanoic acid (31 obtained from Preparation Example 57) mg, 0.092 mM) from 5- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline (20 mg, 0.099 mM) obtained by reference to the method of WO 03/093231 of Preparation 45 Using the experimental method, 12 mg (0.023 mM) of the title compound were obtained in 25% yield.

Mass (EI) 520 (M ⁺ +1)

Example  28: 1-{(2S) -2-amino-4-oxo-4- [5- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl] butyl} -5 Of 5,5-difluoropiperidin-2-one hydrochloride

T-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3-oxo-3- [5- (tri obtained from Production Example 70 6 mg (0.012) of the title compound from the fluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl] propyl} carbamate (12 mg, 0.023 mM) using the experimental method of Example 23 mM) was obtained in 57% yield.

NMR: ¹ H-NMR (CD ₃ OD) δ 7.61-7.38 (3H, m), 4.79-4.78 (2H, m), 3.84-3.75 (4H, m), 3.67-3.62 (2H, m), 3.48- 3.46 (1H, m), 3.15-3.12 (1H, m), 3.04-3.02 (1H, m), 2.81-2.70 (1H, m), 2.66-2.56 (3H, m), 2.41-2.32 (2H, m )

Mass (EI) 420 (M ⁺ +1)

Production Example  71: t-butyl {(1S) -1-{[(2S) -2-methyl-5-oxomorpholin-4-yl] methyl} -3-oxo-3- [5- (t Refluoromethyl ) -3,4- Dehydroisocunoline -2 (1H) -yl] propyl} Carbamate synthesis

(3S) -3-[(t-butoxycarboxyl) amino] -4-[(2S) -2-methyl-5-oxopiperidinemorpholin-4-yl] butanoic acid obtained from Production Example 55 ( 31 mg, 0.097 mM) from 5- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline (20 mg, 0.099 mM) obtained by reference to the method of WO 03/093231 Example 45 Using the experimental method of 10 mg (0.020 mM) of the title compound was obtained in 20% yield.

Mass (EI) 500 (M ⁺ +1)

Example  29: (6S) -4-{(2S) -2-amino-4-oxo-4- [5- ( Trifluoromethyl ) -3,4- Dehydroisocunoline Synthesis of -2 (1H) -yl] butyl} -6-methylmorpholin-3-one hydrochloride

T-butyl {(1S) -1-{[(2S) -2-methyl-5-oxomorpholin-4-yl] methyl} -3-oxo-3- [5- (trifluoro) obtained from Preparation Example 76 Romethyl) -3,4-dihydroisoquinolin-2 (1H) -yl] propyl} carbamate (10 mg, 0.020 mM) using the experimental method of Example 23 6 mg (0.013 mM) of the title compound. ) In 65% yield

NMR: ¹ H-NMR (CD ₃ OD) δ 7.61-7.40 (3H, m), 4.87-4.79 (2H, m), 4.20-4.07 (2H, m), 3.94-3.90 (1H, m), 3.82- 3.76 (2H, m), 3.66-3.49 (3H, m), 3.40-3.35 (2H, m), 3.14-3.00 (2H, m), 2.73-2.60 (2H, m), 1.24 (3H, d, J = 6 Hz)

Mass (EI) 400 (M ⁺ +1)

Production Example  72: t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3- [2- (4-  Fluorophenyl )-4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -3- Oxopropyl } Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxomorpholine-1- obtained from Preparation Example 57 2- (4-fluorophenyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [16] (0.067 mM) obtained from Japanese-butanoic acid and [58] 20 mg (0.067 mM) of 3,4-d] pyrimidine hydrochloride were reacted to give 22 mg (53% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 8.48-8.46 (2H, m), 7.18-7.16 (2H, m), 5.79-5.77 (1H, m), 4.94-4.88 (1H, m), 4.82-4.72 (1H, m), 4.21 (1H, brs), 3.94-3.88 (1H, m), 3.80-3.70 (3H, m), 3.62-3.58 (1H, m), 3.12-3.03 (2H, m), 2.87-2.82 ( 1H, m), 2.60-2.52 (4H, m), 2.28-2.23 (2H, m), 1.41-1.40 (9H, m)

Mass (m / e) 516 (M + 1-BOC)

Example  30: 1-{(2S) -2-amino-4- [2- (4-fluorophenyl) -4- (trifluoromethyl) -5,8-di Hydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -4- Oxobutyl } -5,5- Difluoropiperidine Synthesis of 2-one

In the same manner as in Example 22, t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3- [obtained from Preparation Example 72. 2- (4-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] -3-oxopropyl} Carbamate 15.3 mg (yield 78%) of the title compound were obtained from 22 mg (0.036 mM).

¹ H NMR (CD ₃ OD) δ 8.49-8.48 (2H, m), 7.23-7.20 (2H, m), 4.90-4.85 (2H, m), 3.95-3.70 (5H, m), 3.50-3.46 (1H , m), 3.30-3.28 (1H, m), 3.13 (1H, brs), 3.03 (1H, brs), 2.90-2.86 (1H, m), 2.76-2.72 (1H, m), 2.58-2.54 (2H , m), 2.37-2.32 (2H, m)

Mass (m / e) 516 (M + 1)

Production Example  73: t-butyl [(1S) -3- [2- (4-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydrate Ropyrido [3,4-d] pyrimidine -7 (6H) -yl] -1-{[(2S) -2- methyl -5- Oxomorpholine -4-day] methyl } 3- jade Small profile] Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(2S) -2-methyl-5-oxomorpholin-4- obtained from Preparation Example 55 2- (4-fluorophenyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido obtained from 21.2 mg (0.067 mM) of 1] -butanoic acid and Preparation 58 20 mg (0.067 mM) of 3,4-d] pyrimidine hydrochloride were reacted to give 26 mg (yield 40%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 8.49-8.46 (2H, m), 7.17-7.15 (2H, m), 5.81-5.76 (1H, m), 4.96-4.88 (1H, m), 4.83-4.72 (1H, m), 4.23-4.09 (3H, m), 3.93-3.85 (2H, m), 3.79 (1H, brs), 3.68-3.61 (1H, m), 3.54-3.48 (1H, m), 3.39-3.30 ( 2H, m), 3.10-3.03 (3H, m), 2.60-2.53 (1H, m), 1.42-1.41 (9H, m), 1.25 (3H, d, J = 6.1 Hz),

Mass (m / e) 496 (M + 1-BOC)

Example  31: (6S) -4-{(2S) -2-amino-4- [2- (4-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3, Synthesis of 4-d] pyrimidin-7 (6H) -yl] -4-oxobutyl} -6-methylmorpholin-2-one

T-butyl [(1S) -3- [2- (4-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydropyripy obtained from Preparation 73 in the same manner as in Example 22 Fig. [3,4-d] pyrimidin-7 (6H) -yl] -1-{[(2S) -2-methyl-5-oxomorpholin-4-yl] methyl} 3-oxopropyl] carba Mate 17.8 mg (77% yield) of the title compound were obtained from 26 mg (0.044 mM).

¹ H NMR (CD ₃ OD) δ 8.49-8.48 (2H, m), 7.24-7.21 (2H, m), 4.97-4.85 (2H, m), 4.20-4.10 (2H, m), 3.96-3.93 (2H , m), 3.87-3.84 (1H, m), 3.79 (1H, brs), 3.67-3.55 (2H, m), 3.33-3.30 (2H, m), 2.13 (1H, brs), 3.03 (1H, brs ), 2.91-2.87 (1H, m), 2.76-2.71 (1H, m), 1.24-1.22 (3H, m)

Mass (m / e) 496 (M + 1)

Production Example  74: t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3- {2- (3- Fluorophenyl )-4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl} -3- Oxopropyl } Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxomorpholine-1- obtained from Preparation Example 57 2- (3-fluorophenyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido obtained from 22.6 mg (0.067 mM) of 1] -butanoic acid and Preparation 60 20 mg (0.067 mM) of 3,4-d] pyrimidine hydrochloride were reacted to give 27 mg (72% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 8.29-8.25 (1H, m), 8.18-8.15 (1H, m), 7.53-7.44 (1H, m), 7.24-7.19 (1H, m) 5.81-5.79 (1H, m ), 4.99-4.88 (1H, m), 4.85-4.75 (1H, m), 4.23 (1H, brs), 3.94-3.91 (1H, m), 3.81-3.67 (4H, m), 3.64-3.58 (2H , m), 3.12-3.06 (2H, m), 2.88-2.84 (1H, m), 2.63-2.54 (3H, m), 2.27-2.24 (1H, m), 1.43-1.41 (9H, m).

Mass (m / e) 516 (M + 1-BOC)

Example  32: 1-{(2S) -2-amino-4- [2- (3-fluorophenyl) -4- (trifluoromethyl) -5,8-di Hydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -4- Oxobutyl } -5,5- Difluoropiperidine Synthesis of 2-one

In the same manner as in Example 22, t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3- {obtained from Preparation Example 74. 2- (3-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl} -3-oxopropyl} 18.5 mg (76% yield) of the title compound were obtained from 27 mg (0.044 mM) of carbamate.

¹ H NMR (CD ₃ OD) δ 8.31-8.28 (1H, m), 8.16-8.12 (1H, m), 7.57-7.51 (1H, m), 7.31-7.26 (1H, m) 5.00-4.88 (2H, m), 3.99-3.88 (2H, m), 3.85-3.77 (2H, m), 3.58-3.53 (1H, m), 3.51-3.46 (2H, m), 3.16 (1H, brs), 3.06 (1H, brs), 2.75-2.70 (1H, m), 2.63-2.52 (3H, m), 2.40-2.32 (2H, m).

Mass (m / e) 516 (M + 1)

Production Example  75: t-butyl [(1S) -3- [2- (3-fluorophenyl) -4- (trifluoro) -5,8-dihydropy Lido [3,4-d] pyrimidine -7 (6H) -yl] -1-{[(2S) -2- methyl -5- Oxomorpholine -4-day] methyl } -3- Oxo profile] Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(2S) -2-methyl-5-oxomorpholin-4- obtained from Preparation Example 55 2- (3-fluorophenyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido obtained from 21.2 mg (0.067 mM) of 1] -butanoic acid and Preparation 60 20 mg (0.067 mM) of 3,4-d] pyrimidine hydrochloride were reacted to give 27 mg (yield 68%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 8.33-8.29 (1H, m), 8.22-8.19 (1H, m), 7.54-7.48 (1H, m), 7.28-7.23 (1H, m) 5.86-5.81 (1H, m ), 5.03-4.92 (1H, m), 4.90-4.79 (1H, m), 4.29-4.23 (2H, m), 4.19-4.15 (1H, m), 4.00-3.90 (2H, m), 3.85 (1H) , brs), 3.75-3.68 (1H, m), 3.59-3.52 (1H, m), 3.45-3.35 (2H, m), 3.15-3.10 (2H, m), 2.96-2.90 (1H, m), 2.64 -2.60 (1H, m), 1.47-1.46 (9H, m), 1.32-1.28 (3H, m).

Mass (m / e) 496 (M + 1-BOC)

Example  33: (6S) -4-{(2S) -2-amino-4- [2- (3- Fluorophenyl )-4-( Trifluoromethyl Synthesis of 5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] -4-oxobutyl} -6-methylmorpholin-3-one

T-butyl [(1S) -3- [2- (3-fluorophenyl) -4- (trifluoro) -5,8-dihydropyrido obtained from Preparation Example 75 in the same manner as in Example 22 [3,4-d] pyrimidin-7 (6H) -yl] -1-{[(2S) -2-methyl-5-oxomorpholin-4-yl] methyl} -3-oxopropyl] carba Mate 16.5 mg (68% yield) of the title compound were obtained from 27 mg (0.045 mM).

¹ H NMR (CD ₃ OD) δ 8.30-8.28 (1H, m), 8.16-8.12 (1H, m), 7.57-7.51 (1H, m), 7.31-7.26 (1H, m) 5.01-4.88 (2H, m), 4.21-4.09 (2H, m), 4.00-3.84 (3H, m), 3.64-3.54 (2H, m), 3.46-3.35 (3H, m), 3.16 (1H, brs), 3.06 (1H, brs), 2.78-2.72 (1H, m), 2.64-2.57 (1H, m), 1.27-1.24 (3H, m).

Mass (m / e) 496 (M + 1)

Production Example  76: t-butyl [(1S) -3- [2- (4-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydrate Ropyrido [3,4-d] pyrimidine -7 (6H) -yl] -1-{[(5R) -5- methyl -2- Oxopiperidine -1 day] methyl } -3-jade Sopro Phil] Carbamate  synthesis

In the same manner as in Production Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(5R) -5-methyl-2-oxopiperidine-1 obtained from Production Example 51 -Yl] -butanoic acid 30 (0.094 mM) and 2- (4-fluorophenyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido obtained from Preparation Example 58 28 mg (0.094 mM) of [3,4-d] pyrimidine hydrochloride were reacted to give 29 mg (yield 52%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 8.50-8.46 (2H, m), 7.26-7.00 (2H, m) 5.88-5.87 (1H, m), 4.92 (1H, s), 4.86-4.74 (1H, m), 4.21 (1H, brs), 3.92 (1H, brs), 3.82-3.79 (1H, m), 3.64-3.52 (2H, m), 3.38-3.35 (1H, m), 3.10-3.04 (3H, m), 2.87-2.85 (1H, m), 2.55-2.45 (1H, m), 2.41-2.21 (2H, m), 1.95-1.88 (1H, m), 1.82-1.80 (1H, m), 1.43-1.41 (10H , m), 1.01-0.99 (3H, m)

Mass (m / e) 494 (M + 1-BOC)

Example  34: (5R) -1-{(2S) -2-amino-4- [2- (4-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3, 4-d] pyrimidin-7 (6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one

T-butyl [(1S) -3- [2- (4-fluorophenyl) -4- (trifluoromethyl) -5,8-dihydropyriy obtained from Preparation 76 in the same manner as in Example 22 Fig. [3,4-d] pyrimidin-7 (6H) -yl] -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxopropyl] Carbamate 20 mg (yield 77%) of the title compound were obtained from 29 mg (0.049 mM).

¹ H NMR (CD ₃ OD) δ 8.51-8.48 (2H, m), 7.25-7.20 (2H, m) 4.93-4.86 (2H, m), 3.95-3.92 (1H, m), 3.87-3.84 (1H, m), 3.77-3.76 (1H, m), 3.68-3.61 (1H, m), 3.54-3.50 (1H, m), 3.35-3.32 (1H, m), 3.30-3.29 (1H, m), 3.13- 3.02 (2H, m), 2.90-2.83 (1H, m), 2.75-2.70 (1H, m), 2.44-2.32 (2H, m), 1.99 (1H, brs), 1.82 (1H, brs), 1.52- 1.46 (1 H, m), 1.03-1.01 (3 H, m).

Mass (m / e) 494 (M + 1)

Production Example  77: t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3- [2- (3,4- Difluorophenyl )-4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -3- Oxopropyl } Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidine-1 obtained from Preparation Example 57 -Yl] -butanoic acid 7.0 mg (0.020 mM) and 2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5,6,7,8-tetra obtained from Preparation Example 59 7.0 mg (0.020 mM) of hydropyrido [3,4-d] pyrimidine hydrochloride were reacted to give 6.0 mg (yield 47%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 8.33-8.28 (2H, m), 7.31-7.25 (1H, m) 5.79-5.78 (1H, m), 4.98-4.87 (1H, m), 4.84-4.73 (1H, m ), 4.22-4.21 (1H, m), 3.93-3.91 (1H, m), 3.79-3.64 (3H, m), 3.62-3.56 (2H, m), 3.12-3.05 (2H, m), 2.88-2.84 (1H, m), 2.62-2.54 (3H, m), 2.27-2.24 (2H, m), 1.43-1.41 (9H, m).

Mass (m / e) 534 (M + 1-BOC)

Example  35: 1-{(2S) -2-amino-4- [2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -4- Oxobutyl } -5,5- Difluoropiperidine Synthesis of 2-one

In the same manner as in Example 22, t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3- [obtained from Preparation Example 77 2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] -3- Oxopropyl} carbamate 4.0 mg (74% yield) of the title compound were obtained from 6.0 mg (0.009 mM).

¹ H NMR (CD ₃ OD) δ 8.31-8.28 (2H, m), 7.41-7.39 (1H, m), 4.96-4.85 (2H, m), 3.93-3.84 (2H, m), 3.80-3.74 (2H , m), 3.53-3.49 (1H, m), 3.47-3.44 (2H, m), 3.12 (1H, brs), 3.03 (1H, brs), 2.70-2.66 (1H, m), 2.58-2.52 (3H , m), 2.34-2.32 (2H, m).

Mass (m / e) 534 (M + 1)

Production Example  77: t-butyl [(1S) -3- [2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5,8-di Hydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -1-{[(2S) -2- methyl -5- Oxomorpholine -4-day] methyl } -3-jade Sopro Phil] Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(2S) -2-methyl-5-oxomorpholin-4- obtained from Preparation Example 55 2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro obtained from 6.3 mg (0.020 mM) of general] -butanoic acid and Preparation Example 59 7.0 mg (0.020 mM) of pyrido [3,4-d] pyrimidine hydrochloride were reacted to give 6.0 mg (yield 49%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 8.32-8.24 (2H, m), 7.30-7.23 (1H, m), 5.84-5.79 (1H, m), 4.98-4.74 (2H, m), 4.24-4.19 (2H, m), 4.15-4.09 (1H, m), 3.94-3.84 (2H, m), 3.81 (1H, brs), 3.74-3.67 (1H, m), 3.66-3.46 (1H, m), 3.40-3.31 ( 2H, m), 3.12-3.00 (2H, m), 2.91-2.86 (1H, m), 2.63-2.57 (1H, m), 1.43-1.42 (9H, m), 1.28-1.24 (3H, m).

Mass (m / e) 514 (M + 1-BOC)

Example  36: (6S) -4-{(2S) -2-amino-4- [2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -4- Oxobutyl } -6- Methylmorpholine Synthesis of 3-one

T-butyl [(1S) -3- [2- (3,4-difluorophenyl) -4- (trifluoro) -5,8-di obtained in the same manner as in Example 22 Hydropyrido [3,4-d] pyrimidin-7 (6H) -yl] -1-{[(2S) -2-methyl-5-oxomorpholin-4-yl] methyl} -3-oxopropyl ] Carbamate 6.0 mg (0.012 mM) of 3.6 mg (56% yield) of the title compound were obtained.

¹ H NMR (CD ₃ OD) δ 8.33-8.26 (2H, m), 7.45-7.38 (1H, m), 5.00-4.87 (2H, m), 4.18-4.11 (2H, m), 3.99-3.89 (3H , m), 3.66-3.55 (2H, m), 3.51-3.48 (1H, m), 3.38-3.29 (2H, m), 3.16 (1H, brs), 3.06 (1H, brs), 2.81-2.76 (1H , m), 2.69-2.61 (1H, m), 1.27-1.23 (3H, m).

Mass (m / e) 514 (M + 1)

Production Example  79: t-butyl [(1S) -3- [2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5,8-di Hydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -1-{[(5R) -5- methyl -2- Oxopiperidine -1 day] Me Teal} -3- Oxopropyl ] Carbamate  synthesis

In the same manner as in Production Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(5R) -5-methyl-2-oxopiperidine-1 obtained from Production Example 51 -Yl] -butanoic acid 44 mg (0.139 mM) and 2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5,6,7,8-tetra obtained from Preparation Example 59 49 mg (0.139 mM) of hydropyrido [3,4-d] pyrimidine hydrochloride were reacted to give 82 mg (yield 96%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 8.33-8.26 (2H, m), 7.32-7.25 (1H, m), 5.93-5.92 (1H, m), 5.00-4.90 (1H, m), 4.89-4.77 (1H, m), 4.22 (1H, brs), 3.96-3.93 (1H, m), 3.85-3.82 (1H, m), 3.76-3.55 (2H, m), 3.52-3.48 (2H, m), 3.42-3.38 ( 1H, m), 3.19-3.07 (4H, m), 2.92-2.87 (1H, m), 2.60-2.54 (1H, m), 2.47-2.29 (2H, m), 1.99-1.96 (1H, m), 1.90-1.83 (1H, m), 1.45-1.43 (9H, m), 1.02 (3H, d, J = 6.8 Hz).

Mass (m / e) 512 (M + 1-BOC)

Example  37: (5R) -1-{(2S) -2-Amino-4- [2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -4- Oxobutyl } -5- Methylpiperidine Synthesis of 2-one

T-butyl [(1S) -3- [2- (3,4-difluorophenyl) -4- (trifluoromethyl) -5,8- obtained in the same manner as in Example 22 Dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3- 58.3 mg (79% yield) of the title compound were obtained from 82 mg (0.134 mM) of oxopropyl] carbamate.

¹ H NMR (CD ₃ OD) δ 8.32-8.24 (2H, m), 7.45-7.37 (1H, m), 5.00-4.88 (2H, m), 3.98-3.95 (1H, m), 3.92-3.89 (1H , m), 3.79-3.76 (1H, m), 3.65-3.56 (2H, m), 3.42-3.37 (1H, m), 3.17-3.07 (3H, m), 2.93-2.87 (1H, m), 2.80 -2.76 (1H, m), 2.44-2.36 (2H, m), 2.05-2.02 (1H, m), 1.88-1.85 (1H, m), 1.60-1.49 (1H, m), 1.06-1.04 (3H, m).

Mass (m / e) 512 (M + 1)

Production Example  80: t-butyl  {(1S) -3- [2-cyclopentyl-4- (trifluoromethyl) -5,8-dihydropyri Degree [3,4-d] pyrimidine -7 (6H) -yl] -1-{[(5R) -5- methyl -2- Oxopiperidine -1 day] methyl } -3- Oxo profile} Carbamate  synthesis

In the same manner as in Production Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(5R) -5-methyl-2-oxopiperidine-1 obtained from Production Example 51 -Yl] -butanoic acid 112 mg (0.357 mM) and 2-cyclopentyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- obtained from Preparation Example 62 d] 100 mg (0.325 mM) of pyrimidine hydrochloride were reacted to give 65 mg (yield 84%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 5.88 (1H, brs), 4.88 (1H, s), 4.76-4.64 (1H, m), 4.18 (1H, brs), 3.88 (1H, brs), 3.77 (1H, brs ), 3.63-3.47 (2H, m), 3.39-3.35 (2H, m), 3.01-2.97 (3H, m), 2.88-2.81 (1H, m), 2.55-2.30 (3H, m), 2.17-2.04 (3H, m), 1.93-1.85 (6H, m), 1.70 (2H, brs), 1.42-1.40 (9H, m), 1.00 (3H, d, J = 5.6 Hz).

Mass (m / e) 468 (M + 1-BOC)

Example  38: (5R) -1-{(2S) -2-amino-4- [2- Cyclopentyl -4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one

T-butyl {(1S) -1- [2-cyclopentyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4 obtained from Production Example 80 in the same manner as in Example 22 -d] pyrimidin-7 (6H) -yl] -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxopropyl} carbamate 120 mg (83% yield) of the title compound were obtained from 176 mg (0.310 mM).

¹ H NMR (CD ₃ OD) δ 4.91-4.80 (2H, m), 4.15-4.11 (1H, m), 3.94-3.80 (2H, m), 3.75-3.67 (1H, m), 3.58-3.53 (1H , m), 3.44-3.37 (2H, m), 3.15-3.10 (2H, m), 3.01 (1H, s), 2.96-2.89 (1H, m), 2.81-2.72 (1H, m), 2.46-2.34 (2H, m), 2.12-2.03 (3H, m), 1.98-1.82 (5H, m), 1.79-1.73 (2H, m), 1.59-1.49 (1H, m), 1.05 (3H, d, J = 6.4 Hz).

Mass (m / e) 468 (M + 1)

Production Example  81: t-butyl [(1S) -3- [2-cyclopentyl-4- (trifluoromethyl) -5,8-dihydropyri Degree [3,4-d] pyrimidine -7 (6H) -yl] -1-{[(2S) -2- methyl -5- Oxomorpholine -4-day] methyl } -3- Oxov Lofil] Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(2S) -2-methyl-5-oxomorpholin-4- obtained from Preparation Example 55 2-cyclopentyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d obtained from 113 mg (0.357 mM) of 1] -butanoic acid and Preparation 62 ] 100 mg (0.325 mM) of pyrimidine hydrochloride gave 180 mg (97% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 5.82-5.77 (1H, m), 4.89-4.78 (1H, m), 4.75-4.63 (1H, m), 4.31-4.19 (2H, m), 4.15-4.09 (1H, m), 3.94-3.84 (2H, m), 3.69 (1H, brs), 3.68-3.62 (1H, m), 3.54-3.45 (1H, m), 3.41-3.30 (2H, m), 3.09-2.98 ( 2H, m), 2.87-2.82 (1H, m), 2.60-2.51 (1H, m), 2.10-2.07 (2H, m), 1.97-1.85 (5H, m), 1.72-1.68 (2H, brs), 1.43-1.42 (9H, m), 1.28-1.24 (3H, m).

Mass (m / e) 470 (M + 1)

Example  39: (6S) -4-{(2S) -2-amino-4- [2-cyclopentyl-4- (trifluoromethyl) -5,8-di Hydropyrido [3,4-d] pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -6-methylmorpholin-3-one

In the same manner as in Example 22, t-butyl [(1S) -3- [2-cyclopentyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4] obtained from Preparation Example 81. -d] pyrimidin-7 (6H) -yl]-1-{[(2S) -2-methyl-5-oxomorpholin-4-yl] methyl} -3-oxopropyl] carbamate 117 mg (79% yield) of the title compound were obtained from 180 mg (0.316 mM).

¹ H NMR (CD ₃ OD) δ 4.83-4.78 (2H, m), 4.22-4.10 (2H, m), 4.00-3.81 (3H, m), 3.69-3.66 (1H, m), 3.59-3.47 (2H , m), 3.45-3.36 (4H, m), 3.10 (1H, brs), 3.00 (1H, brs), 2.82-2.76 (1H, m), 2.68-2.59 (1H, m), 2.12-2.10 (2H , m), 1.97-1.82 (4H, m), 1.79-1.73 (1H, m), 1.26 (3H, d, J = 6.0 Hz).

Mass (m / e) 470 (M + 1)

Production Example  82: t-butyl {(1S) -3- [2-cyclopentyl-4- (trifluoromethyl) -5,8-dihydropyri Degree [3,4-d] pyrimidine -7 (6H) -yl] -1-[(5,5- Difluoro -2- Oxopiperidine -1 day) methyl ] -3- jade Small profile} Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidine-1 obtained from Preparation Example 57 -Yl] -butanoic acid 120 mg (0.357 mM) and 2-cyclopentyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- obtained from Preparation Example 62 d] 100 mg (0.325 mM) of pyrimidine hydrochloride were reacted to give 182 mg (95% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 4.78 (1H, brs), 4.87 (1H, s), 4.77-4.63 (1H, m), 4.20 (1H, brs), 3.89-3.86 (1H, m), 3.75-3.63 (3H, m), 3.60-3.53 (2H, m), 3.41-3.33 (1H, m), 3.05-2.98 (2H, m), 2.82-2.80 (1H, m), 2.60-2.51 (3H, m) , 2.31-2.21 (2H, m), 2.10-2.07 (2H, m), 1.95-1.85 (4H, m), 1.75-1.70 (2H, m), 1.42-1.41 (9H, m).

Mass (m / e) 490 (M + 1-BOC)

Example  40: 1-{(2S) -2-amino-4- [2-cyclopentyl-4- (trifluoromethyl) -5,8-dihydro Pyrido [3,4-d] pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one

T-butyl {(1S) -3- [2-cyclopentyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4 obtained from Preparation Example 82 in the same manner as in Example 22 -d] pyrimidin-7 (6H) -yl] -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3-oxopropyl} carbamate 105 mg (70% yield) of the title compound were obtained from 182 mg (0.309 mM).

¹ H NMR (CD ₃ OD) δ 4.90-4.79 (2H, m), 3.93-3.77 (4H, m), 3.64-3.56 (2H, m), 3.49-3.37 (2H, m), 3.15 (1H, brs ), 3.00 (1H, brs), 2.79-2.73 (1H, m), 2.66-2.52 (3H, m), 2.42-2.31 (2H, m), 2.12-2.08 (2H, m), 1.97-1.83 (4H , m), 1.79-1.73 (2H, m),

Mass (m / e) 490 (M + 1)

Production Example  83: t-butyl-3-amino-4-hydroxy Piperidine -1-carboxylate of  synthesis

(One) t-butyl 3,6- Dihydroxypyridine -1 (2H)- Carboxylate  synthesis

1,2,3,6-tetrahydroxypyridine (1 g, 12 mM) and t-butyl dicarbonate (2.76 g, 12.6 mM) were dissolved in tetrahydrofuran / water (1: 1, 40 ml) for 5 hours. After stirring for a while, ethylacetoacetate (100 ml) was added and washed with water, and then the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2.1 g (11.5 mM) of the title compound in 91% yield.

NMR: ¹ H-NMR (CDCl ₃ ) δ 5.81 (1H, m), 5.66 (1H, m), 3.88 (2H, s), 3.49 (2H, t, J = 6 Hz), 2.13 (2h, brs), 1.47 (9 H, s)

(2) t-butyl 7-oxa-3- Azabicyclo [4.1.0] heptane -3- Carboxylate  synthesis

t-butyl 3,6-dihydroxypyridine-1 (2H) -carboxylate (2.1 g, 11.5 mM) (product of step (1) above) and m-chloroperbenzoic acid (3.1 g, 12.6 mM) It was dissolved in 30 ml of methylene chloride and stirred for 12 hours, ethylacetoacetate (100 ml) was added, washed with water, and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2.0 g (10.0 mM) of the title compound in 87% yield.

Mass (m / e) 200 (M + 1)

(3) t-butyl-3-amino-4- Hydroxypiperidine -One- Carboxylate  synthesis

t-butyl 7-oxa-3-azabicyclo [4.1.0] heptane-3-carboxylate (2.9 g, 10.0 mM) (product of step (2) above) and (S) -1-phenylethylamine (1.2 g, 10.0 mM) was dissolved in 30 ml of water, stirred for 12 hours under reflux, ethylacetoacetate (100 ml) was added and washed with water, and then the organic layer was dried over magnesium sulfate. The solvent was distilled under reduced pressure, dissolved in methanol, and reacted with hydrogen (120 mg) with 20% palladium / carbon for 9 hours under hydrogen. Then, filtered through celite and distilled under reduced pressure, and then obtained by column chromatography to give 0.50 g (2.3 mM) of the title compound in 23% yield.

Mass (m / e) 217 (M + 1)

Production Example  84: 2- [4- (trifluoromethyl) phenyl] -4,5,6,7-tetrahydro [1,3] thiazolo [4,5-c] pyridine Hydrochloride  synthesis

(One) t-butyl  4-hydroxy-3-{[4- ( Trifluoromethyl ) Benzoyl ] Synthesis of amino} piperidine-1-carboxylate

30 ml of methylene chloride with t-butyl 3-amino-4-hydroxypiperidine-1-carboxylate (0.50 g, 2.3 mM) (product of Preparation 83) and triethylamine (0.32 ml, 2.3 mM) 4-trifluoromethyl benzoyl chloride (0.34 ml, 2.3 mM) was slowly added dropwise with stirring at 0 ° C. and stirred for 1 hour, followed by addition of ethyl acetoacetate (100 ml) and washing with water. Dried over magnesium sulfate. After filtration and distillation under reduced pressure, 0.48 g (1.2 mM) of the title compound was obtained by column chromatography in 54% yield.

Mass (m / e) 335 (M + 1)

(2) t-butyl  4-oxo-3-{[4- ( Trifluoromethyl ) Benzoyl ] Synthesis of amino} piperidine-1-carboxylate

0.48 g (1.2 mM) of t-butyl 4-hydroxy-3-{[4- (trifluoromethyl) benzoyl] amino} piperidine-1-carboxylate (product of step (1) above) After dissolving in 10 ml of chloride and adding Dess-Martin peraydinine (5.24 g, 1.9 mM) dropwise and stirring for 5 hours, ethylacetoacetate (50 ml) was added and washed with water, and then the organic layer was washed with magnesium sulfate. Dried. After filtration and distillation under reduced pressure, 0.30 g (0.78 mM) of the title compound was obtained by using column chromatography in 65% yield.

NMR: ¹ H-NMR (CDCl ₃ ) δ 7.94 (2H, d, J = 8 Hz), 7.73 (2H, d, J = 8 Hz), 7.16 (1H, brs), 5.05-5.00 (1H, m), 4.70 ~ 4.60 (1H, m), 4.55-4.45 (1H, m), 3.12-3.00 (1H, m), 2.77-2.66 (2H, m), 2.61-2.57 (2H, m), 1.55 (9H, s)

Mass (m / e) 387 (M + 1)

(3) t-butyl  2- [4- ( Trifluoromethyl ) Phenyl ] -6,7-dihydro [1,3] thiazolo [4,5-c] pyridine-5 (4H)- Carboxylate  synthesis

0.40 g (1.0 mM) of t-butyl 4-oxo-3-{[4- (trifluoromethyl) benzoyl] amino} piperidine-1-carboxylate (product of step (2) above) and Lawesson's reagent 0.47 g (1.2 mM) was dissolved in 30 ml of toluene, stirred under reflux for 4 hours, and then distilled under reduced pressure, followed by column chromatography, to obtain 0.30 g (0.91 mM) of the title compound in 91% yield.

NMR: ¹ H-NMR (CDCl ₃ ) δ 8.00 (2H, d, J = 8 Hz), 7.68 (2H, d, J = 8 Hz), 4.70 (2H, s), 3.79 (2H, s), 2.93 (2H , m), 1.50 (9H, s)

Mass (m / e) 331 (M + 1)

(4) 2- [4- ( Trifluoromethyl ) Phenyl ] -4,5,6,7-tetrahydro [1,3] thiazolo [4,5-c] pyridine Hydrochloride  synthesis

0.30 g of t-butyl 2- [4- (trifluoromethyl) phenyl] -6,7-dihydro [1,3] thiazolo [4,5-c] pyridine-5 (4H) -carboxylate ( 0.91 mM) (product of step (3)) was dissolved in 15 ml of 4.0 M HCl / dioxane solution, stirred for 2 hours, distilled under reduced pressure and 0.15 g (0.53 mM) of the title compound was purified by column chromatography. Obtained in% yield.

NMR: ¹ H-NMR (CD ₃ OD) δ 8.08 (2H, d, J = 8 Hz), 7.77 (2H, d, J = 8 Hz), 4.03 (2H, s), 3.16 (2H, t, J = 6 Hz ), 2.96 (2H, m)

Mass (m / e) 285 (M + 1)

Production Example  88: t-butyl [(1S) -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxo-3- {2- [4- ( Trifluoromethyl ) Phenyl ] -6,7- Dihydro [1,3] thiazolo [4,5, c] pyridin-5 (4H) -yl} propyl] Carbamate  synthesis

(3S) -3-[(t-butoxycarbonyl) amino] -4-[(5R) -5-methyl-2-oxopiperidin-1-yl] -butanoic acid obtained from Preparation Example 51 30.0 2- [4- (trifluoromethyl) phenyl] -4,5,6,7-tetrahydro [1,3] thiazolo [4,5-c] pyridine obtained from mg (0.095 mM) and Preparation Example 68 30.0 mg (0.095 mM) was used to obtain 30 mg (yield 13%) of the title compound in the same manner as in Preparation 45.

NMR: ¹ H-NMR (CDCl ₃ ) δ 8.00 (2H, m), 7.69 (2H, m), 5.84 (1H, m), 4.84 (1H, s), 4.70 (1H, m), 4.22 (1H, m), 4.03 to 3.89 (1H, m), 3.81 (1H, t, J = 6hz), 3.65 (1H, m), 3.52 (2H, m), 3.36 (1H, m), 3.10 to 2.80 (4H, m), 2.55 to 2.35 (3H, m), 1.95 (1H, m), 1.80 (1H, m), 1.42 (9H, s), 1.00 (3H, m)

Mass (m / e) 581 (M + 1)

Example 41: (5R) -1-[(2S) -2-amino-4-oxo-4- {2- [4- (trifluoromethyl) phenyl] -6,7 -dihydro [1,3 ] Thiazolo [4,5, c] pyridin-5 (4H) -yl} butyl ] -5 -methylpiperidin- 2-one

T-butyl [(1S) -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxo-3- {2- [4 obtained from Preparation Example 85. -(Trifluoromethyl) phenyl] -6,7-dihydro [1,3] thiazolo [4,5, c] pyridin-5 (4H) -yl} propyl] carbamate 5 mg (0.0086 mM) To give 1.2 mg (29% yield) of the title compound in the same manner as in Example 3.

NMR: ¹ H-NMR (CD ₃ OD) δ 8.12 (2H, d, J = 8 Hz), 7.80 (2H, d, J = 8 Hz), 4.85 (1H, s), 4.79 (1H, s), 4.03 ( 1H, t, J = 6 Hz), 3.89 (2H, m), 3.79 (1H, m), 3.55 (1H, m), 3.36 (1H, m), 3.13 (2H, m), 2.98 (2H, m) , 2.81 (1H, m), 2.42 (2H, m), 2.03 (1H, m), 1.86 (1H, m), 1.53 (9H, s), 1.05 (3H, d, J = 7 Hz)

Mass (m / e) 481 (M + 1)

Example 42: (6S) -4-[(2S) -2-amino-4-oxo-4- {2- [4- (trifluoromethyl) phenyl] -6,7 -dihydro [1,3 ] Thiazolo [4,5, c] pyridin-5 (4H) -yl} butyl ] -6- methylmorpholin - 3-one

45 mg (0.14 mM) of compound 2- [4- (trifluoromethyl) phenyl] -4,5,6,7-tetrahydro [1,3] thiazolo [4,5-c] pyridine of Preparation Example 84 ) And (3S) -3-[(t-butoxycarbonyl) amino] -4-[(2S) -2-methyl-5-oxomorpholin-4-yl] -butanoic acid obtained from Preparation Example 55 29 mg (yield 43%) of the title compound were obtained using the procedure of Preparation Example 45 and Example 3 in turn from 45 mg (0.14 mM).

NMR: ¹ H-NMR (CD ₃ OD) δ 8.12 (2H, d, J = 8 Hz), 7.79 (2H, d, J = 8 Hz), 4.85 (1H, s), 4.79 (1H, s), 4.20 ( 2H, m), 4.02 (1H, t, J = 6 Hz), 3.98 (1H, m), 3.90 (1H, M), 3.88 (1H, m), 3.72 (1H, m), 3.60 (1H, m) , 3.38 (2H, m), 3.09 (1H, m), 2.99 (1H, m), 2.96 (1H, m), 2.77 (1H, m), 1.26 (3H, d, J = 6 Hz)

Mass (m / e) 483 (M + 1)

Example  43: 1-[(2S) -2-amino-4-oxo-4- {2- [4- (trifluoromethyl) phenyl] -6,7-dihydro [1,3] thiazolo [4,5, c] pyridin-5 (4H) -yl} Butyl ] -5,5-difluoro Piperidine 2-on

45 mg (0.14 mM) of compound 2- [4- (trifluoromethyl) phenyl] -4,5,6,7-tetrahydro [1,3] thiazolo [4,5-c] pyridine of Preparation Example 84 (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidin-1-yl] -butanoic acid obtained from Preparation Example 57 45 mg (yield 64%) of the title compound were obtained using the methods of Preparation 45 and Example 3 in turn from 47 mg (0.14 mM).

NMR: ¹ H-NMR (CD ₃ OD) δ 8.12 (2H, d, J = 8 Hz), 7.79 (2H, d, J = 8 Hz), 4.85 (1H, s), 4.79 (1H, s), 4.02 ( 1H, t, J = 6Hz), 3.90 (2H, m), 3.81 (3H, m), 3.50 (1H, m), 3.09 (1H, m), 3.00 (1H, m), 2.91 (1H, m) , 2.62 (2H, m), 2.37 (2H, m)

Mass (m / e) 503 (M + 1)

Production Example  89: 2- (4- Fluorophenyl ) -4,5,6,7- Tetrahydro [1,3] thiazolo [4,5, c] pyridine hydrochloride

Preparation 84 from 0.20 g (0.92 mM) of compound t-butyl-3-amino-4-hydroxypiperidine-1-carboxylate and 0.11 ml (0.92 mM) of 4-fluorobenzoyl chloride of Preparation Example 83 The method gave 70 mg (yield 32%) of the title compound.

NMR: ¹ H-NMR (CD ₃ OD) δ 7.90 (2H, m), 7.20 (2H, m), 4.98 (2H, s), 3.13 (2H, t, J = 6 Hz), 2.89 (2H, m)

Mass (m / e) 235 (M + 1)

Example  44: (5R) -1-{(2S) -2-amino-4- [2- (4- Fluorophenyl ) -6,7-dihydro [1,3] Thiazolo [4,5, c] pyridine -5 (4H) -yl] -4- Oxobutyl } -5- Methylpiperidine 2-on

10 mg (0.037 mM) of compound 2- (4-fluorophenyl) -4,5,6,7-tetrahydro [1,3] thiazolo [4,5, c] pyridine of Preparation 86 and Preparation 51 12.0 mg (0.037) of (3S) -3-[(t-butoxycarbonyl) amino] -4-[(5R) -5-methyl-2-oxopiperidin-1-yl] -butanoic acid mM) to give 5.8 mg (yield 36%) of the title compound by using the method of Preparation 45 and Example 3.

NMR: ¹ H-NMR (CD ₃ OD) δ 7.92 (2H, m), 7.20 (2H, m), 4.78 (1H, s), 4.71 (1H, s), 3.98 (1H, m), 3.89 (2H , m), 3.71 (1H, m), 3.51 (1H, m), 3.36 (1H, m), 3.13 (2H, m), 2.98 (2H, m), 2.80 (1H, m), 2.38 (2H, m), 1.98 (1H, m), 1.82 (1H, m), 1.50 (9H, s), 1.00 (3H, m)

Mass (m / e) 431 (M + 1)

Example  45: (6S) -4-{(2S) -2-amino-4-oxo-4- [2- (4-fluorophenyl) 6,7-dihydro [1,3] Seeazolo [4,5, c] pyridin-5 (4H) -yl] butyl} -6- Methylmorpholine -3-one

10 mg (0.037 mM) of compound 2- (4-fluorophenyl) -4,5,6,7-tetrahydro [1,3] thiazolo [4,5, c] pyridine of Preparation Example 86 12.0 mg (0.037) of (3S) -3-[(t-butoxycarbonyl) amino] -4-[(2S) -2-methyl-5-oxomorpholin-4-yl] -butanoic acid obtained from 55 mM) to give 5.0 mg (yield 31%) of the title compound using the method of Preparation 45 and Example 3.

NMR: ¹ H-NMR (CD ₃ OD) δ 7.91 (2H, m), 7.18 (2H, m), 4.78 (1H, s), 4.71 (1H, s), 4.15 (2H, m), 4.02 (1H , t, J = 6 Hz), 3.91 (2H, m), 3.81 (2H, M), 3.70 (1H, m), 3.65 (2H, m), 3.55 (1H, m), 3.00 (2H, m), 2.93 (1H, m), 2.80 (1H, m), 1.22 (3H, m)

Mass (m / e) 433 (M + 1)

Example  46: 1-{(2S) -2-amino-4- [2- (4-fluorophenyl) -6,7-dihydro [1,3] thiazolo [4,5, c] pyridine-5 ( 4H) -yl] -4- Oxobutyl } -5,5-difluoro Piperidine 2-on

10 mg (0.037 mM) of compound 2- (4-fluorophenyl) -4,5,6,7-tetrahydro [1,3] thiazolo [4,5, c] pyridine of Preparation 86 and Preparation 57 14.0 mg (0.037) of (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidin-1-yl] -butanoic acid mM) to give 8.0 mg (yield 48%) of the title compound using the methods of Preparation 45 and Example 3.

NMR: ¹ H-NMR (CD ₃ OD) δ 7.91 (2H, dm), 7.20 (2H, m), 4.79 (1H, s), 4.71 (1H, s), 3.95 (1H, m), 3.90 (3H , m), 3.82 (2H, m), 3.45 (1H, m), 3.00 (2H, m), 2.92 (1H, m), 2.80 (1H, m), 2.59 (2H, m), 2.34 (2H, m)

Mass (m / e) 453 (M + 1)

Production Example  87: 2- ( Tetrahydro -2H-pyran-4-yl) -4,5,6,7-tetrahydro [1,3] Cazole in[ 4,5, c] pyridine

0.22 g (1.0 mM) of compound t-butyl-3-amino-4-hydroxypiperidine-1-carboxylate of Preparation Example 83 and 0.15 mg (1.0 mM) of tetrahydro-2H-pyran-4-carbonylchloride 45 mg (yield 17%) of the title compound were obtained using the method of Preparation 45 from.

Mass (m / e) 225 (M + 1)

Example  47: (5R) -1-{(2S) -2-Amino-4-oxo-4- [2- (tetrahydro-2H-pyran-4-yl) -6,7-dihydro [1,3] thiazolo [4,5, c] pyridin-5 (4H) -yl] Butyl } -5- Methylpiperidine 2-on

8.0 mg (0.031 mM) of compound 2- (tetrahydro-2H-pyran-4-yl) -4,5,6,7-tetrahydro [1,3] thiazolo [4,5, c] pyridine of Preparation Example 87 ) And (3S) -3-[(t-butoxycarbonyl) amino] -4-[(5R) -5-methyl-2-oxopiperidin-1-yl] -butano obtained from Preparation Example 51 3.2 mg (yield 25%) of the title compound were obtained using the procedures of Preparation Example 45 and Example 42 in turn from 9.6 mg (0.031 mM) of Iksan.

NMR: ¹ H-NMR (CD ₃ OD) δ 4.73 (1H, s), 4.65 (1H, s), 4.03 (2H, m), 3.96 (1H, t, J = 6 Hz), 3.83 (2H, m) , 3.76 (1H, m), 3.69 (1H, m), 3.60 (3H, m), 3.52 (1H, m), 3.35 (1H, m), 3.25 (1H, m), 3.11 (1H, m), 2.97 (1H, m), 2.88 (2H, m), 2.75 (1H, m), 2.43 (2H, m), 1.99 (2H, m), 1.85 (2H, m), 1.55 (1H, m), 1.05 (3H, d, J = 7 Hz)

Mass (m / e) 421 (M + 1)

Example  48: (6S) -4-{(2R) -2-amino-4-oxo-4- [2- (tetrahydro-2H-pyran-4-yl) -6,7-dihydro [1,3] thiazolo [4,5, c] pyridin-5 (4H) -yl] Butyl } -6- Methylmorpholine -3-one

8.0 mg (0.031 mM) of compound 2- (tetrahydro-2H-pyran-4-yl) -4,5,6,7-tetrahydro [1,3] thiazolo [4,5, c] pyridine of Preparation Example 87 ) And (3S) -3-[(t-butoxycarbonyl) amino] -4-[(2S) -2-methyl-5-oxomorpholin-4-yl] -butanoic acid obtained from Preparation Example 55 2.5 mg (yield 19%) of the title compound were obtained by using the methods of Preparation 45 and Example 42 in turn from 10 mg (0.031 mM).

NMR: ¹ H-NMR (CD ₃ OD) δ 4.88 (1H, s), 4.66 (1H, s), 4.21 (2H, m), 4.05 (2H, m), 3.95 (2H, m), 3.83 (1H , m), 3.75 (1H, m), 3.58 (4H, m), 3.36 (2H, m), 3.25 (1H, m), 2.97 (1H, m), 2.86 (2H, m), 2.68 (1H, m), 2.00 (2H, m), 1.85 (2H, m), 1.26 (3H, d, J = 7 Hz)

Mass (m / e) 423 (M + 1)

Example  49: 1-{(2S) -2-amino-4-oxo-4- [2- (tetrahydro-2H-pyran-4-yl) -6,7-dihydro [1,3] thiazolo [4,5, c] pyridin-5 (4H) -yl] Butyl } -5,5-difluoro Piperidine 2-on

8.0 mg (0.031 mM) of compound 2- (tetrahydro-2H-pyran-4-yl) -4,5,6,7-tetrahydro [1,3] thiazolo [4,5, c] pyridine of Preparation Example 87 ) And (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidin-1-yl] -butano obtained from Preparation Example 57 3.6 mg (yield 26%) of the title compound were obtained using the procedures of Preparation Example 45 and Example 3 in turn from 10 mg (0.031 mM) of Iksan.

NMR: ¹ H-NMR (CD ₃ OD) δ 4.88 (1H, s), 4.73 (1H, s), 4.03 (2H, m), 3.95 (1H, t, J = 6 Hz), 3.83 (2H, m) , 3.77 (3H, m), 3.58 (2H, m), 3.48 (1H, m), 3.25 (1H, m), 2.97 (1H, m), 2.88 (2H, m), 2.70 (1H, m), 2.61 (2H, m), 2.37 (2H, m), 2.01 (2H, m), 1.85 (2H, m)

Mass (m / e) 443 (M + 1)

Production Example  88: 2- ( Trifluoromethyl 4,5,6,7- Tetrahydro [1,3] thiazolo [4,5, c] pyridine

Preparation 84 from 0.30 g (1.4 mM) and 0.19 ml (1.4 mM) of trifluoroacetic anhydride of the compound t-butyl-3-amino-4-hydroxypiperidine-1-carboxylate of Preparation Example 84 Using the method of 20 mg (yield 9.3%) of the title compound.

NMR: ¹ H-NMR (CDCl ₃ ) δ 4.52 (2H, brs), 3.64 (2H, brs), 3.41 (2H, brs)

Mass (m / e) 209 (M + 1)

Example  50: (6S) -4-{(2S) -2-amino-4-oxo-4- [2- (trifluoromethyl) -6,7-dihydro [1,3] thiazolo [4,5, c] pyridin-5 (4H) -yl] Butyl } -6- Methylmorpholine -3-one

Obtained from compound 55 (0.032 mM) of compound 2- (trifluoromethyl) 4,5,6,7-tetrahydro [1,3] thiazolo [4,5, c] pyridine of Preparation Example 88 and Preparation 55 From 11 mg (0.032 mM) of (3S) -3-[(t-butoxycarbonyl) amino] -4-[(2S) -2-methyl-5-oxomorpholin-4-yl] -butanoic acid 2.0 mg (yield 15%) of the title compound were obtained in succession using the methods of Preparation 45 and Example 3.

NMR: ¹ H-NMR (CD ₃ OD) δ 4.80 (1H, s), 4.75 (1H, s), 4.11 (3H, m), 3.95 (2H, m), 3.85 (2H, m), 3.80 (1H , m), 3.67 (1H, m), 3.56 (2H, m), 3.08 (1H, m), 2.99 (1H, m), 2.89 (1H, m), 2.72 (1H, m)

Mass (m / e) 407 (M + 1)

Example  51: 1-{(2S) -2-amino-4-oxo-4- [2- (trifluoromethyl) -6,7-dihydro [1,3] thiazolo [4,5, c] pyridine -5 (4H) -day] Butyl } -5,5-difluoro Piperidine 2-on

Obtained from Preparation Example 57 with 5.0 mg (0.032 mM) of Compound 2- (trifluoromethyl) 4,5,6,7-tetrahydro [1,3] thiazolo [4,5, c] pyridine and (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidin-1-yl] -butanoic acid 11 mg (0.032 mM) 3.0 mg (yield 22%) of the title compound were obtained using the procedure of Preparation Example 45 and Example 3 in turn.

NMR: ¹ H-NMR (CD ₃ OD) δ 4.82 (1H, s), 4.75 (1H, s), 3.96 (1H, t, J = 6 Hz), 3.85 (2H, m), 3.80 (1H, m) , 3.72 (2H, m), 3.45 (1H, m), 3.08 (1H, m), 2.99 (1H, m), 2.85 (1H, m), 2.72 (1H, m), 2.57 (2H, m), 2.33 (2H, m)

Mass (m / e) 427 (M + 1)

Production Example  89: 2- (2-methoxyethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine  Synthesis of Hydrochloride

(One) 3- Of methoxy propane imidamide  synthesis

Trimethyl aluminum (11.7 ml, 23.4 mmol, 2.0 M toluene solution) was added dropwise to 20 ml of toluene with ammonium chloride (1.26 g, 23.4 mmol) at room temperature. After stirring for 1.5 hours, 3-methoxypropanenitrile (2 g, 23.4 mmol) was added thereto and heated at 85 ° C. for 9 hours. After the reaction, the solution was cooled, poured into 100 ml of chloroform containing 200 g of silica gel, filtered, washed with 100 ml of methanol, and distilled to give 2.35 g (23 mmol) of the title compound in 98% yield.

NMR: ¹ H-NMR (CD ₃ OD) δ 3.70 (2H, t, J = 7.0 Hz), 3.39 (3H, s), 2.73 (2H, t, J = 7.0 Hz)

(2) t-butyl 2- (2- Methoxyethyl )-4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pi Limidine-7 (6H)- Carboxylate  synthesis

500 mg (1.69 mmol) of t-butyl 3-oxo-4- (trifluoroacetyl) piperidine-1-carboxylate obtained in Preparation Example 47 and 3-methoxypropaneimida obtained in step (1). 173 mg (1.69 mmol) of mead were heated to 90 ° C. in 20 ml pyridine and stirred for about 1.5 hours. After cooling to room temperature, pyridine was removed under reduced pressure to purify the impure title compound by column chromatography (10: 1 hexane: ethyl acetate) to give 220 mg (yield 36%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 4.69 (2H, s), 3.90 (2H, t, J = 7.0 Hz), 3.70 (2H, t, J = 5.5 Hz), 3.35 (3H, s), 3.23 (2H, t, J = 7.0 Hz), 2.97 (2H, br s), 1.47 (9H, s)

Mass (m / e) 362 (M + 1)

(3) 2- (2- Methoxyethyl )-4-( Trifluoromethyl ) -5,6,7,8- Tetrahydropyrido [3,4-d] pi Synthesis of Limidine Hydrochloride

T-butyl 2- (2-methoxyethyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 (6H) obtained in step (2) above 120 mg (0.609 mmol) of) -carboxylate gave 120 mg of the title compound in the same manner as in Preparation 58 (3) (yield 75%).

¹ H NMR (CD ₃ OD) δ 4.51 (2H, s), 3.93 (2H, t, J = 6.0 Hz), 3.63 (2H, t, J = 6.0 Hz), 3.2-3.4 (7H, m)

Mass (m / e) 262 (M + 1)

Production Example  90: 2- (cyclopropylmethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyri Degree [3,4-d] pyrimidine  Synthesis of Hydrochloride

(One) Of cyclopropylethaneimidamid  synthesis

In the same manner as in Preparation Example 89 (1), 2.061 g (25 mmol) of cyclopropyl acetonitrile was used to obtain 1.61 g (yield 66%) of the title compound.

NMR: ¹ H-NMR (CD ₃ OD) δ 2.39 (2H, d, J = 7.2 Hz), 1.09 (1H, m), 0.66 (2H, m), 0.35 (2H, m)

(2) t-butyl 2- ( Cyclopropylmethyl )-4-( Trifluoromethyl ) -5,8- Dehydropyri Degree[ 3,4-d] pyrimidine -7 (6H)- Carboxylate  synthesis

In the same manner as in Preparation Example 89 (2), 500 mg (1.69 mmol) of t-butyl 3-oxo-4- (trifluoroacetyl) piperidine-1-carboxylate (product of Preparation 47) 166 mg (1.69 mmol) of cyclopropylethaneimidamid obtained in step (1) were used to obtain 155 mg (yield 26%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 4.70 (2H, s), 3.71 (2H, t, J = 6.0 Hz), 2.98 (2H, br s), 2.84 (2H, d, J = 7.5 Hz), 1.49 (9H , s), 1.25 (1H, m), 0.51 (2H, m), 0.29 (2H, m)

Mass (m / e) 358 (M + 1)

(3) 2-( Cyclopropylmethyl )-4-( Trifluoromethyl ) -5,6,7,8- Tetrahydropyri Degree[ 3,4-d] pyrimidine  Synthesis of Hydrochloride

In the same manner as in Production Example 58 (3), t-butyl 2- (cyclopropylmethyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3, 155 mg (0.43 mmol) of 4-d] pyrimidine-7 (6H) -carboxylate gave 85 mg (yield 76%) of the title compound.

¹ H NMR (CD ₃ OD) δ 4.33 (2H, s), 3.37 (2H, t, J = 6.5 Hz), 2.63 (2H, d, J = 6.0 Hz), 1.0 (1H, m), 0.30 (2H , m), 0.1 (2H, m)

Mass (m / e) 258 (M + 1)

Production Example  91: 2-pyridin-4-yl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- d] pyrimidine  Synthesis of Hydrochloride

(One) Pyridine-4- Of carboxymidamide  synthesis

In the same manner as in Preparation Example 89 (1), 2.0 g (19.2 mmol) of isoninicotinonitrile was used to obtain 1.06 g (yield 45%) of the title compound.

NMR: ¹ H-NMR (CD ₃ OD) δ 8.86 (2H, m), 7.79 (2H, m)

(2) t-butyl 2-pyridin-4-yl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 (6H)- Carboxylate  synthesis

In the same manner as in Preparation Example 89 (2), 500 mg (1.69 mmol) of t-butyl 3-oxo-4- (trifluoroacetyl) piperidine-1-carboxylate (product of Preparation 47) 210 mg (1.69 mmol) of pyridine-4-carboximidamide obtained from step (1) were used to obtain 240 mg (yield 37%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 8.78 (2H, d, J = 5.5 Hz), 8.30 (2H, d, J = 5.5 Hz), 4.81 (2H, s), 3.76 (2H, t, J = 6.0 Hz) , 3.07 (2H, br s), 1.51 (9H, s)

Mass (m / e) 381 (M + 1)

(3) 2-pyridin-4-yl-4- ( Trifluoromethyl ) -5,6,7,8- Tetrahydropyrido [3,4-d] pi Synthesis of Limidine Hydrochloride

In the same manner as in Preparation Example 58 (3), t-butyl 2-pyridin-4-yl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4] obtained from step (2). 240 mg (0.63 mmol) of pyrimidine-7 (6H) -carboxylate gave 160 mg (90% yield) of the title compound.

¹ H NMR (CD ₃ OD) δ 9.07 (2H, d, J = 6.0 Hz), 9.02 (2H, d, J = 6.0 Hz), 4.71 (2H, s), 3.70 (2H, br t, J = 6.0 Hz), 3.43 (2H, broad singlet)

Mass (m / e) 281 (M + 1)

Production Example  92: 2- (4- Fluorobenzyl )-4-( Trifluoromethyl ) -5,6,7,8- Tetrahydro  Pipe Degree [3,4-d] pyrimidine  Synthesis of Hydrochloride

(One) 2- (4- Fluorophenyl ) Of ethane imidamide  synthesis

In the same manner as in Preparation Example 89 (1), 2.0 g (yield 89%) of the title compound was obtained using 2.0 g (14.8 mmol) of (4-fluorophenyl) acetonitrile.

NMR: ¹ H-NMR (CD ₃ OD) δ 7.50 (2H, m), 7.15 (2H, m), 3.90 (2H, s)

(2) t-butyl 2- (4- Fluorobenzyl )-4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4- d] pyrimidine-7 (6H)- Carboxylate  synthesis

In the same manner as in Production Example 89 (2), 500 mg (1.69 mmol) of t-butyl 3-oxo-4- (trifluoroacetyl) piperidine-1-carboxylate and 2 obtained from step (1) were used. 250 mg (yield 36%) of the title compound were obtained using 258 mg (1.69 mmol) of-(4-fluorophenyl) ethaneimidamid.

¹ H NMR (CDCl ₃ ) δ 7.37 (2H, m), 6.95 (2H, t, J = 8.0 Hz), 4.67 (2H, s), 4.24 (2H, s), 3.69 (2H, t, J = 6.0 Hz), 2.96 (2H, br s), 1.49 (9H, s)

Mass (m / e) 412 (M + 1)

(3) 2- (4- Fluorobenzyl )-4-( Trifluoromethyl ) -5,6,7,8- Tetrahydropyrido [3,4- d] Synthesis of pyrimidine hydrochloride

In the same manner as in Production Example 58 (3), t-butyl 2- (4-fluorobenzyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3] was obtained from step (2). 77 mg (yield 41%) of the title compound were obtained using 250 mg (0.61 mmol) of 4-4-d] pyrimidine-7 (6H) -carboxylate.

¹ H NMR (CD ₃ OD) δ 7.35 (2H, m), 6.99 (2H, t, J = 9.0 Hz), 4.45 (2H, s), 4.27 (2H, s), 3.57 (2H, t, J = 6.5 Hz), 3.23 (2H, t, J = 6.5 Hz)

Mass (m / e) 312 (M + 1)

Production Example  93: 2- (3-thienyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- d] pyrimidine  Synthesis of Hydrochloride

(One) Thiophene-3- Of carboxymidamide  synthesis

In the same manner as in Production Example 89 (1), 1.81 g (15 mmol) of the title compound were obtained using 1.64 g (15 mmol) of thiophene-3-carbonitrile.

NMR: ¹ H-NMR (CD ₃ OD) δ 8.41 (1H, m), 7.69 (1H, m), 7.59 (1H, m)

(2) t-butyl 2- (3- Thienyl )-4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrides Midine-7 (6H)- Carboxylate  synthesis

In the same manner as in Preparation Example 89 (2), 500 mg (1.69 mmol) of t-butyl 3-oxo-4- (trifluoroacetyl) piperidine-1-carboxylate and the tee obtained from step (1) were used. 228 mg (yield 35%) of the title compound were obtained using 214 mg (1.69 mmol) of offen-3-carboximidamide.

¹ H NMR (CDCl ₃ ) δ 8.34 (1H, m), 7.90 (1H, m), 7.38 (1H, m), 4.74 (2H, s), 3.74 (2H, t, J = 6.0 Hz), 3.00 ( 2H, br s), 1.51 (9H, s)

Mass (m / e) 386 (M + 1)

(3) 2- (3- Thienyl )-4-( Trifluoromethyl ) -5,6,7,8- Tetrahydropyrido [3,4-d] pyrimi Synthesis of Dean Hydrochloride

In the same manner as in Production Example 58 (3), t-butyl 2- (3-thienyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3, 168 mg (Yield 61%) of the title compound were obtained using 228 mg (0.59 mmol) of 4-d] pyrimidine-7 (6H) -carboxylate.

¹ H NMR (CD ₃ OD) δ 8.42 (1H, m), 7.86 (1H, m), 7.53 (1H, m), 4.53 (2H, s), 3.62 (2H, t, J = 6.5 Hz), 3.30 (2H, m)

Mass (m / e) 286 (M + 1)

Production Example  94: 2- (2-thienyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- d] pyrimidine  Synthesis of Hydrochloride

(One) Thiophene-2- Of carboxymidamide  synthesis

In the same manner as in Preparation Example 89 (1), 1.8 g (yield 95%) of the title compound was obtained using 1.64 g (15 mmol) of thiophene-2-carbonitrile.

NMR: ¹ H-NMR (CD ₃ OD) δ 7.94 (1H, m), 7.89 (1H, m), 7.24 (1H, m)

(2) t-butyl 2- (2- Thienyl )-4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrides Midine-7 (6H)- Carboxylate  synthesis

In the same manner as in Preparation Example 89 (2), 500 mg (1.69 mmol) of t-butyl 3-oxo-4- (trifluoroacetyl) piperidine-1-carboxylate (product of Preparation 47) 146 mg (1.69 mmol) of thiophene-2-carboxyimidamide obtained from step (1) were used to obtain 144 mg (25% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 8.04 (1H, d, J = 4.0 Hz), 7.50 (1H, d, J = 5.0 Hz), 7.14 (1H, m), 4.72 (2H, s), 3.72 (2H, t, J = 5.5 Hz), 2.99 (2H, br s), 1.54 (9H, s)

Mass (m / e) 386 (M + 1)

(3) 2- (2- Thienyl )-4-( Trifluoromethyl ) -5,6,7,8- Tetrahydropyrido [3,4-d] pyrides Synthesis of Midine Hydrochloride

In the same manner as in Preparation Example 58 (3), t-butyl 2- (2-thienyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3, 144 mg (0.42 mmol) of 4-d] pyrimidine-7 (6H) -carboxylate gave 72 mg (61% yield) of the title compound.

¹ H NMR (CD ₃ OD) δ 8.09 (1H, m), 7.72 (1H, m), 7.23 (1H, m), 4.55 (2H, s), 3.64 (2H, t, J = 6.5 Hz), 3.30 (2H, m)

Mass (m / e) 286 (M + 1)

Production Example  95: 2- (2-furyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d] Pyrimidine  Synthesis of Hydrochloride

(One) Furan -2- Of carboxymidamide  synthesis

In the same manner as in Preparation Example 89 (1), 2.1 g (yield 64%) of the title compound was obtained by using 2.77 g (30 mmol) of 2-puronitrile.

NMR: ¹ H-NMR (CD ₃ OD) δ 7.94 (1H, s), 7.58 (1H, d, J = 3.6 Hz), 6.78 (1H, m)

(2) t-butyl 2- (2- Furyl )-4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -car Leboxile Synthesis of sites

In the same manner as in Production Example 89 (2), 3 g (10.2 mmol) of t-butyl 3-oxo-4- (trifluoroacetyl) piperidine-1-carboxylate (product of Preparation 47) and the above 1.12 g (10.2 mmol) of furan-2-carboxymidamide obtained in step (1) were used to obtain 2.55 g (yield 68%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 7.65 (1H, s), 7.39 (1H, d, J = 3.0 Hz), 6.58 (1H, m), 4.78 (2H, s), 3.73 (2H, t, J = 5.5 Hz), 3.0 (2H, br s), 1.49 (9H, s)

Mass (m / e) 370 (M + 1)

(3) 2- (2- Furyl )-4-( Trifluoromethyl ) -5,6,7,8- Tetrahydropyrido [3,4-d] pyrimi Synthesis of Dean Hydrochloride

In the same manner as in Production Example 58 (3), t-butyl 2- (2-furyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4] obtained from step (2). -d] pyrimidine-7 (6H) -carboxylate 2.55 g (6.9 mmol) gave 1.42 g (yield 67%) of the title compound.

¹ H NMR (CD ₃ OD) δ 7.58 (1H, s), 7.43 (1H, d, J = 3.7 Hz), 6.67 (1H, m), 4.51 (2H, s), 3.61 (2H, t, J = 6.5 Hz), 3.26 (2H, t, J = 6.5 Hz)

Mass (m / e) 270 (M + 1)

Production Example  96: 2- (3- Furyl )-4-( Trifluoromethyl ) -5,6,7,8- Tetrahydropyrido [3,4-d] pyrimidine  Synthesis of Hydrochloride

(One) Furan -3- Of carboxymidamide  synthesis

In the same manner as in Preparation Example 89 (1), 1.56 g (yield 94%) of the title compound were obtained using 1.4 g (15 mmol) of 3-puronitrile.

NMR: ¹ H-NMR (CD ₃ OD) δ 8.4 (1H, s), 7.76 (1H, m), 6.96 (1H, m)

(2) t-butyl 2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 (6H)- Carboxylate  synthesis

In the same manner as in Preparation Example 89 (2), 500 mg (1.69 mmol) of t-butyl 3-oxo-4- (trifluoroacetyl) piperidine-1-carboxylate (product of Preparation 47) 186 mg (1.69 mmol) of furan-3-carboximidamide obtained from step (1) were used to obtain 170 mg (yield 27%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 8.26 (1H, s), 7.49 (1H, s), 7.06 (1H, s), 4.70 (2H, s), 3.72 (2H, t, J = 5.5 Hz), 3.0 ( 2H, br s), 1.54 (9H, s)

Mass (m / e) 370 (M + 1)

(3) 2- (3- Furyl )-4-( Trifluoromethyl ) -5,6,7,8- Tetrahydropyrido [3,4-d] pyrimi Synthesis of Dean Hydrochloride

In the same manner as in Production Example 58 (3), t-butyl 2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4] obtained from step (2). -d] 86 mg (yield 69%) of the title compound were obtained using 170 mg (0.46 mmol) of pyrimidine-7 (6H) -carboxylate.

¹ H NMR (CD ₃ OD) δ 8.39 (1H, s), 7.67 (1H, m), 7.09 (1H, m), 4.54 (2H, s), 3.65 (2H, t, J = 6.0 Hz), 3.29 (2H, t, J = 6.0 Hz)

Mass (m / e) 270 (M + 1)

Production Example  97: 2-pyridin-3-yl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- d] pyrimidine  Synthesis of Hydrochloride

(One) t-butyl 2-pyridin-3-yl-4- ( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrides Midine-7 (6H)- Carboxylate  synthesis

In the same manner as in Production Example 89 (2), 700 mg (2.37 mmol) of t-butyl 3-oxo-4- (trifluoroacetyl) piperidine-1-carboxylate (product of Preparation 47) and the 370 mg (2.37 mmol) of pyridine-3-carboximidamide obtained from step (1) were used to obtain 640 mg (yield 71%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 9.65 (1H, s), 8.73 (2H, m), 7.43 (1H, m), 4.80 (2H, s), 3.76 (2H, t, J = 5.5 Hz), 3.05 ( 2H, br s), 1.51 (9H, s)

Mass (m / e) 381 (M + 1)

(2) 2-pyridin-3-yl-4- ( Trifluoromethyl ) -5,6,7,8- Tetrahydropyrido [3,4-d] pi Synthesis of Limidine Hydrochloride

In the same manner as in Preparation Example 58 (3), t-butyl 2-pyridin-3-yl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4] obtained from step (2). -d] 500 mg (yield 94%) of the title compound were obtained using 640 mg (1.68 mmol) of pyrimidine-7 (6H) -carboxylate.

¹ H NMR (CD ₃ OD) δ 9.72 (1H, s), 9.49 (1H, m), 9.00 (1H, br s), 8.23 (1H, m), 4.67 (2H, s), 3.66 (2H, t , J = 5.5 Hz), 3.39 (2H, broad singlet)

Mass (m / e) 281 (M + 1)

Production Example  98: 2- (1H-pyrrol-2-yl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine  Synthesis of Hydrochloride

(One) 1H-pyrrole-2- Of carboxymidamide  synthesis

1.09 g (yield 67%) of the title compound were obtained in the same manner as in Preparation Example 89 (1), using 1.38 g (15 mmol) of 1H-pyrrole-2-carbonitrile.

NMR: ¹ H-NMR (CD ₃ OD) δ 7.12 (2H, m), 6.31 (1H, t, J = 3.3 Hz)

(2) t-butyl 2- (1H-pyrrol-2-yl) -4- ( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] Pyrimidine-7 (6H)- Carboxylate  synthesis

In the same manner as in Preparation Example 89 (2), 800 mg (2.7 mmol) of t-butyl 3-oxo-4- (trifluoroacetyl) piperidine-1-carboxylate (product of Preparation 47) and the 300 mg (2.7 mmol) of 1H-pyrrole-2-carboxymidamide obtained from step (1) were used to obtain 185 mg (yield 19%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 7.14 (1H, m), 6.98 (1H, m), 6.34 (1H, m), 7.18 (1H, m), 4.67 (2H, s), 3.71 (2H, t, J = 5.5 Hz), 2.95 (2H, br s), 1.49 (9H, s)

Mass (m / e) 369 (M + 1)

(3) 2- (1H-pyrrole-2-yl) -4- ( Trifluoromethyl ) -5,6,7,8- Tetrahydropyrido [3,4-d] Synthesis of Pyrimidine Hydrochloride

In the same manner as in Production Example 58 (3), t-butyl 2- (1H-pyrrol-2-yl) -4- (trifluoromethyl) -5,8-dihydropyrido obtained from step (2) 185 mg (0.50 mmol) of [3,4-d] pyrimidine-7 (6H) -carboxylate gave 48 mg (yield 36%) of the title compound.

¹ H NMR (CD ₃ OD) δ 11.25 (1H, m), 7.08 (1H, m), 7.00 (1H, m), 6.26 (1H, m), 4.45 (2H, s), 3.59 (2H, t, J = 5.5 Hz), 3.20 (2H, t, J = 5.5 Hz)

Mass (m / e) 269 (M + 1)

Production Example  99: t-butyl [(1S) -3- [2- (2-methoxyethyl) -4-trifluoromethyl] -5,8-dihydro Pyrido [3,4-d] pyrimidine -7 (6H) -yl] -1-{[(5R) -5- methyl -2- Oxopiperidine -1 day] methyl } -3-oxopropyl] Carbamate  synthesis

(3S) -3-[(t-butoxycarbonyl) amino] -4-[(5R) -5-methyl-2-oxopiperidin-1-yl] -butanoic acid 44.0 from Preparation Example 51 2- (2-methoxyethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d] pyridine obtained from mg (0.139 mmole) and Preparation 89 61 mg (yield 79%) of the title compound were obtained in the same manner as in Preparation Example 45 using 37.5 mg (0.126 mmole) of midine hydrochloride.

¹ H NMR (CDCl ₃ ) δ 5.89-5.87 (1H, m), 4.90-4.79 (1H, m), 4.78-4.67 (1H, m), 4.20-4.15 (1H, m), 3.92-3.82 (2H, m), 3.78-3.75 (1H, m), 3.64-3.47 (4H, m), 3.39-3.36 (4H, m), 3.26-3.23 (2H, m), 3.11-2.99 (3H, m), 2.87- 2.80 (1H, m), 2.55-2.27 (3H, m), 1.97-1.93 (1H, m), 1.84-1.81 (1H, m), 1.42-1.41 (9H, m), 1.00 (3H, d, J = 5.6 Hz).

Mass (m / e) 558 (M + 1)

Example  52: (5R) -1-{(2S) -2-amino-4- [2- (2- Methoxyethyl )-4-( Trifluoromethyl Synthesis of) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one

T-butyl [(1S) -3- [2- (2-methoxyethyl) -4-trifluoromethyl] -5,8-dihydropyrido [3,4-d] pyrile obtained from Preparation Example 99. Midin-7 (6H) -yl] -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxopropyl] carbamate 61 mg (0.109 mmole) In the same manner as in Example 22 using 51.9 mg (96% yield) of the title compound.

¹ H NMR (CD ₃ OD) δ 4.92-4.80 (2H, m), 3.94-3.83 (4H, m), 3.67 (1H, brs), 3.54-3.53 (2H, m), 3.42-3.34 (4H, m ), 3.24-3.21 (2H, m), 3.12-3.01 (3H, m), 2.82-2.77 (1H, m), 2.70 -2.60 (1H, m), 2.47-2.32 (2H, m), 2.05-2.00 (1H, m), 1.88-1.85 (1H, m), 1.59-1.48 (1H, m), 1.04 (3H, d, J = 6.4 Hz).

Mass (m / e) 458 (M + 1)

Production Example  100: t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3- [2- (2- Methoxyethyl )-4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -3- Oxopropyl } Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidine-1 obtained from Preparation Example 57 -Yl] -butanoic acid, 47.0 mg (0.139 mmole), and 2- (2-methoxyethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido obtained from Preparation Example 89. Separation and purification using 37.5 mg (0.126 mmole) of [3,4-d] pyrimidine hydrochloride gave 47 mg (yield 58%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 5.79-5.78 (1H, m), 4.90-4.79 (1H, m), 4.76-4.65 (1H, m), 4.25-4.20 (1H, m), 3.92-3.86 (3H, m), 3.80-3.68 (3H, m), 3.63-3.53 (2H, m), 3.36 (3H, s), 3.26-3.23 (2H, m), 3.01-2.99 (2H, m), 2.85-2.78 ( 1H, m), 2.61-2.50 (3H, m), 2.32-2.20 (2H, m), 1.42-1.41 (9H, m)

Mass (m / e) 580 (M + 1)

Example  53: 1-{(2S) -2-amino-4- [2- (2- Methoxyethyl )-4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one

In the same manner as in Example 22, t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3- [obtained from Preparation Example 100 2- (2-methoxyethyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] -3-oxopropyl} 47 mg (0.081 mmole) of carbamate gave 25.4 mg (61%) of the title compound.

¹ H NMR (CD ₃ OD) δ 4.86-4.80 (2H, m), 3.94-3.90 (3H, m), 3.89-3.75 (3H, m), 3.57-3.45 (3H, m), 3.34-3.32 (3H , m), 3.24-3.21 (2H, m), 3.11-3.01 (2H, m), 2.73-2.51 (4H, m), 2.41-2.30 (2H, m)

Mass (m / e) 480 (M + 1)

Production Example  101: t-butyl {(1S) -3- [2- (cyclopropylmethyl) -4- (trifluoromethyl) -5,8-di Hydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -1-{[(5R) -5- methyl -2- Oxopiperidine -1 day] Me  Teal} -3- Oxopropyl } Carbamate  synthesis

In the same manner as in Production Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(5R) -5-methyl-2-oxopiperidine-1 obtained from Production Example 51 -Yl] -butanoic acid 2- (cyclopropylmethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3 from 50.0 mg (0.159 mmole) and Preparation 90 , 4-d] pyrimidine hydrochloride 43.0 mg (0.145 mmole) was purified by separation to give 66 mg (yield 75%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 5.88 (1H, brs), 4.90-4.80 (1H, m), 4.78-4.66 (1H, m), 4.20-4.18 (1H, m), 3.93-3.85 (1H, m) , 3.79-3.76 (1H, m), 3.65-3.47 (2H, m), 3.43-3.33 (1H, m), 3.11-2.99 (3H, m), 2.86-2.81 (3H, m), 2.56-2.27 ( 3H, m), 2.02-1.93 (1H, m), 1.84-1.81 (1H, m), 1.42-1.41 (9H, m), 1.30-1.17 (2H, m), 1.00 (3H, d, J = 6.4 Hz), 0.55-0.49 (2H, m), 0.34-0.28 (2H, m)

Mass 554 (m / e) (M + 1)

Example  54: (5R) -1-{(2S) -2-Amino-4- [2- (cyclopropylmethyl) -4- (trifluoromethyl) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -4- Oxobutyl } -5- Methylpiperidine Synthesis of 2-one

In the same manner as in Example 22, t-butyl {(1S) -3- [2- (cyclopropylmethyl) -4- (trifluoromethyl) -5,8-dihydropyrido [obtained from Preparation Example 101 [ 3,4-d] pyrimidin-7 (6H) -yl] -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxopropyl} carba 47.9 mg (82% yield) of the title compound were obtained from 66 mg (0.119 mmole) of mate.

¹ H NMR (CD ₃ OD) δ 4.68-4.56 (2H, m), 3.70-3.58 (2H, m), 3.40-3.37 (1H, m), 3.31-3.21 (2H, m), 3.17-3.12 (1H , m), 2.87-2.77 (3H, m), 2.62-2.60 (2H, m), 2.53-2.48 (1H, m), 2.41-2.35 (1H, m), 2.20-2.11 (2H, m), 1.79 -1.76 (1H, m), 1.63-1.59 (1H, m), 1.34-1.23 (1H, m), 1.06-0.97 (1H, m), 0.80 (3H, d, J = 6.4 Hz), 0.31-0.23 (2H, m), 0.11-0.04 (2H, m),

Mass (m / e) 454 (M + 1)

Production Example  102: t-butyl {(1S) -3- [2- (cyclopropylmethyl) -4- (trifluoromethyl) -5,8-di Hydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -1-[(5,5- Difluoro -2- Oxopiperidine -1-yl) methyl] -3- Oxopropyl } Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidine-1 obtained from Preparation Example 57 -Yl] -butanoic acid, 53.5 mg (0.159 mmole), and 2- (cytopropylmethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido obtained from Preparation Example 90 [ Purified and separated using 43.0 mg (0.145 mmole) of 3,4-d] pyrimidine hydrochloride to give 66 mg (yield 75%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 5.77 (1H, brs), 4.87-4.80 (1H, m), 4.73-4.62 (1H, m), 4.19 (1H, brs), 3.89-3.86 (1H, m), 3.78 -3.68 (3H, m), 3.61-3.55 (2H, m), 3.05-2.92 (2H, m), 2.84-2.79 (3H, m), 2.59-2.47 (3H, m), 2.29-2.15 (2H, m), 1.40-1.39 (9H, m), 1.24-1.23 (1H, m), 0.53-0.49 (2H, m), 0.28-0.27 (2H, m).

Mass (m / e) 576 (M + 1)

Example  55: 1-{(2S) -2-amino-4- [2- (cyclopropylmethyl) -4- (trifluoromethyl) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -4- Oxobutyl } -5,5- Difluoropiperidine Synthesis of 2-one

In the same manner as in Example 22, t-butyl {(1S) -3- [2- (cyclopropylmethyl) -4- (trifluoromethyl) -5,8-dihydropyrido [obtained from Preparation Example 102 [ 3,4-d] pyrimidin-7 (6H) -yl] -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3-oxopropyl} carba 61 mg (0.106 mmole) of mate gave 35.9 mg (66% yield) of the title compound.

¹ H NMR (CD ₃ OD) δ 4.67-4.55 (2H, m), 3.62-3.54 (4H, m), 3.30-3.23 (3H, m), 2.87-2.77 (2H, m), 2.62-2.60 (2H , m), 2.48-2.27 (4H, m), 2.17-2.06 (2H, m), 1.03-0.98 (1H, m), 0.31-0.26 (2H, m), 0.07-0.04 (2H, m)

Mass (m / e) 476 (M + 1)

Production Example  103: t-butyl {(1S) -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxo-3- [2-pyridin-4-yl -4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] propyl} Carbamate  synthesis

In the same manner as in Production Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(5R) -5-methyl-2-oxopiperidine-1 obtained from Production Example 51 -Yl] -butanoic acid 44.0 mg (0.140 mmole) and 2-pyridin-4-yl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3] from Preparation Example 91 , 4-d] pyrimidine hydrochloride 45.0 mg (0.127 mmole) was purified by separation to give 50 mg (yield 62%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 8.80-8.79 (2H, m), 8.31 (2H, m), 5.89 (1H, brs), 5.03-4.79 (2H, m), 4.20 (1H, brs), 3.94 (1H , brs), 3.70 (1H, brs), 3.60-3.46 (2H, m), 3.39-3.36 (1H, m), 3.17-3.04 (3H, m), 2.87 (1H, brs), 2.56-2.51 (1H , m), 2.44-2.31 (2H, m), 1.96 (1H, brs), 1.82 (2H, brs), 1.43-1.41 (9H, m), 1.00 (3H, d, J = 6.4 Hz).

Mass 577 (m / e) (M + 1)

Example  56: (5R) -1-{(2S) -2-amino-4-oxo-4- [2-pyridin-4-yl-4- ( Trifluoromethyl Synthesis of) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] butyl} -5-methylpiperidin-2-one

T-butyl {(1S) -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxo obtained in the same manner as in Example 22 -3- [2-pyridin-4-yl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] propyl} carba 33.6 mg (81% yield) of the title compound were obtained from 50 mg (0.087 mmole) of mate.

¹ H NMR (CD ₃ OD) δ 8.77-8.75 (2H, m), 8.44-8.42 (2H, m), 5.05-4.93 (2H, m), 3.98-3.91 (2H, m), 3.57-3.39 (4H , m), 3.22-3.20 (1H, m), 3.12-3.05 (2H, m), 2.78-2.73 (1H, m), 2.66-2.58 (1H, m), 2.47-2.32 (2H, m), 2.05 -2.03 (1H, m), 1.88-1.84 (1H, m), 1.60-1.48 (1H, m), 1.06-1.03 (3H, m).

Mass (m / e) 477 (M + 1)

Production Example  104: t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3-oxo-3- [2-pyridin-4-yl -4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] propyl} Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidine-1 obtained from Preparation Example 57 -Yl] -butanoic acid 47.0 mg (0.140 mmole) and 2-pyridin-4-yl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3] from Preparation Example 91 , 4-d] pyrimidine hydrochloride 45.0 mg (0.127 mmole) was purified by separation to give 65 mg (yield 78%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 8.81 (2H, brs), 8.32-8.31 (2H, m), 5.81 (1H, brs), 4.98-4.96 (1H, m), 4.85-4.83 (1H, m), 4.23 (1H, brs), 3.95 (1H, brs), 3.81-3.73 (3H, m), 3.62-3.49 (2H, m), 3.16-3.10 (2H, m), 2.89-2.85 (1H, m), 2.62 -2.55 (3H, m), 2.28 (2H, m), 1.42 (9H, s)

Mass (m / e) 599 (M + 1)

Example  57: 1-{(2S) -2-amino-4-oxo-4- [2-pyridin-4-yl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d] Synthesis of pyrimidin-7 (6H) -yl] butyl} -5,5-difluoropiperidin-2-one

In the same manner as in Example 22, t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3-oxo obtained from Preparation Example 104 -3- [2-pyridin-4-yl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] propyl} carba 34.4 mg (64% yield) of the title compound were obtained from 65 mg (0.109 mmole) of mate.

¹ H NMR (CD ₃ OD) δ 8.77-8.75 (2H, m), 8.45-8.43 (2H, m), 5.06-4.86 (2H, m), 4.00-3.88 (2H, m), 3.85-3.78 (2H , m), 3.58-3.49 (3H, m), 3.21-3.11 (2H, m), 2.75-2.70 (1H, m), 2.64-2.54 (3H, m), 2.37-2.33 (2H, m)

Mass (m / e) 499 (M + 1)

Production Example  105: t-butyl [(1S) -3- [2- (4-fluorobenzyl) -4- (trifluoromethyl) -5,8-dich Dropyrido [3,4-d] pyrimidine -7 (6H) -yl] -1-{[(5R) -5- methyl -2- Oxopiperidine -1 day] methyl } -3-jade Sopro Phil] Carbamate  synthesis

In the same manner as in Production Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(5R) -5-methyl-2-oxopiperidine-1 obtained from Production Example 51 2- (4-fluorobenzyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido obtained from 38.0 mg (0.120 mmole) of -yl] -butanoic acid and Preparation 92. Separation and purification using 38.0 mg (0.109 mmole) of [3,4-d] pyrimidine hydrochloride gave 70 mg (yield 96%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 7.34-7.32 (2H, m), 7.00-6.96 (2H, m), 5.86-5.85 (1H, m), 4.85-4.80 (1H, m), 4.73-4.61 (1H, m), 4.23-4.15 (2H, m), 3.86-3.83 (1H, m), 3.74-3.68 (1H, m), 3.56-3.47 (2H, m), 3.36-3.33 (1H, m), 3.06- 2.95 (3H, m), 2.85-2.77 (1H, m), 2.50-2.83 (4H, m), 1.92 (1H, brs), 1.79 (2H, brs), 1.40-1.38 (9H, m), 0.99 ( 3H, d, J = 6.7 Hz).

Mass (m / e) 608 (M + 1)

Example  58: (5R) -1-{(2S) -2-amino-4- [2- (4- Fluorobenzyl )-4-( Trifluoromethyl Synthesis of) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one

T-butyl [(1S) -3- [2- (4-fluorobenzyl) -4- (trifluoromethyl) -5,8-dihydropyriy obtained from Preparation Example 105 in the same manner as in Example 22 Fig. [3,4-d] pyrimidin-7 (6H) -yl] -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxopropyl] 49.7 mg (85% yield) of the title compound were obtained from 77 mg (0.115 mmole) of carbamate.

¹ H NMR (CD ₃ OD) δ 7.39-7.36 (2H, m), 7.04-7.00 (2H, m), 4.86-4.77 (2H, m), 4.28-4.27 (2H, m), 3.86-3.83 (2H , m), 3.50-3.37 (4H, m), 3.09-2.99 (3H, m), 2.73-2.66 (1H, m), 2.61-2.53 (1H, m), 2.43-2.29 (2H, m), 2.02 -1.98 (1H, m), 1.85-1.82 (1H, m), 1.56-1.46 (1H, m), 1.03 (3H, d, J = 6.4 Hz).

Mass (m / e) 508 (M + 1)

Production Example  106: t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3- [2- (4- Fluorobenzyl )-4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -3- Oxopropyl } Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidine-1 obtained from Preparation Example 57 2- (4-fluorobenzyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido obtained from 40.3 mg (0.120 mmole) of -yl] -butanoic acid and Preparation 92. Separation and purification using 38.0 mg (0.109 mmole) of [3,4-d] pyrimidine hydrochloride gave 66 mg (yield 87%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 7.35-7.26 (2H, m), 7.00-6.97 (2H, m), 5.77-5.75 (1H, m), 4.85-4.80 (1H, m), 4.70-4.61 (1H, m), 4.24-4.18 (3H, m), 3.86-3.84 (1H, m), 3.76-3.67 (2H, m), 3.59-3.48 (3H, m), 3.07-2.97 (2H, m), 2.83- 2.76 (1H, m), 2.57-2.49 (3H, m), 2.28-2.19 (2H, m) 1.40 (9H, s)

Mass (m / e) 630 (M + 1-Boc)

Example  59: 1-{(2S) -2-amino-4- [2- (4-fluorobenzyl) -4- (trifluoromethyl) -5,8-di Hydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -4- Oxobutyl } -5,5- Difluoropiperidine Synthesis of 2-one

In the same manner as in Example 22, t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3- [obtained from Preparation Example 106 2- (4-fluorobenzyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] -3-oxopropyl} 44.4 mg (80% yield) of the title compound were obtained from 66.0 mg (0.105 mmole) of carbamate.

¹ H NMR (CD ₃ OD) δ 7.39-7.36 (2H, m), 7.04-7.00 (2H, m), 4.89-4.81 (2H, m), 4.28-4.27 (2H, m), 3.88-3.77 (4H , m), 3.53-3.47 (3H, m), 3.09-2.99 (2H, m), 2.66-2.61 (1H, m), 2.58-2.49 (3H, m), 2.40-2.29 (2H, m)

Mass (m / e) 530 (M + 1)

Production Example  107: t-butyl {(1S) -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxo-3- [2- (3- Thienyl )-4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] propyl} Carbamate  synthesis

In the same manner as in Production Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(5R) -5-methyl-2-oxopiperidine-1 obtained from Production Example 51 -Yl] -butanoic acid 43.0 mg (0.137 mmole) and 2- (3-thienyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido obtained from Preparation Example 95 [ Purified and purified using 40.0 mg (0.124 mmole) of 3,4-d] pyrimidine hydrochloride to give 75.0 mg (yield 94%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 8.38-8.37 (1H, m), 7.93-7.91 (1H, m), 7.43-7.40 (1H, m), 5.90-5.88 (1H, m), 5.33 (1H, s) , 4.92-4.74 (1H, m), 4.23-4.13 (1H, m), 3.98-3.92 (1H, m), 3.84-3.81 (1H, m), 3.73-3.51 (2H, m), 3.42-3.28 ( 1H, m), 3.13-3.04 (3H, m), 2.93-2.87 (1H, m), 2.59-2.54 (1H, m), 2.48-2.32 (2H, m), 2.00-1.84 (3H, m), 1.46-1.44 (9H, m) 1.04-1.03 (3H, m).

Mass (m / e) 582 (M + 1)

Example  60: (5R) -1-{(2S) -2-amino-4-oxo-4- [2- (3-thienyl) -4- (trifluoromethyl) -5,8-dihydropyrido Synthesis of [3,4-d] pyrimidin-7 (6H) -yl] butyl} -5-methylpiperidin-2-one

T-butyl {(1S) -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxo obtained in the same manner as in Example 22 from Production Example 107 -3- [2- (3-thienyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] propyl} carbox 54.4 mg (88% yield) of the title compound were obtained from 75.0 mg (0.129 mmole) of bamate.

¹ H NMR (CD ₃ OD) δ 8.41-8.40 (1H, m), 7.90-7.88 (1H, m), 7.54-7.52 (1H, m), 4.97-4.86 (2H, m), 3.96-3.86 (2H , m), 3.67-3.63 (1H, m), 3.57-3.45 (2H, m), 3.42-3.37 (1H, m), 3.13-3.03 (3H, m), 2.80-2.76 (1H, m), 2.68 -2.59 (1H, m), 2.46-2.32 (2H, m), 2.01 (1H, brs), 1.84-1.82 (1H, m), 1.58-1.51 (1H, m), 1.06-1.03 (3H, m)

Mass (m / e) 482 (M + 1)

Production Example  108: t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3-oxo-3- [2- (3- Thienyl )-4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] propyl} Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidine-1 obtained from Preparation Example 57 -Yl] -butanoic acid 43 mg (0.137 mmole) and 2- (3-thienyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido obtained from Preparation Example 93 [ 3,4-d] pyrimidine hydrochloride was separated and purified using 40.0 mg (0.124 mmole) to obtain 66.0 mg (yield 80%) of the title compound.

¹ H NMR (CD ₃ OD) δ 8.35-8.34 (1H, m), 7.89-7.87 (1H, m), 7.40-7.37 (1H, m), 5.79-5.77 (1H, m), 4.88 (1H, s ), 4.80-4.69 (1H, m), 4.23 (1H, brs), 3.92-3.89 (1H, m), 3.78-3.66 (3H, m), 3.60-3.55 (2H, m), 3.08-3.01 (2H , m), 2.87-2.83 (1H, m), 2.62-2.53 (3H, m), 2.35-2.23 (2H, m), 1.42-1.41 (9H, m)

Mass (m / e) 604 (M + 1)

Example  61: 1-{(2S) -2-amino-4-oxo-4- [2- (3-thienyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4 Synthesis of -d] pyrimidin-7 (6H) -yl] butyl} -5,5-difluoropiperidin-2-one

In the same manner as in Example 22, t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1 yl) methyl] -3-oxo- obtained from Preparation Example 108 3- [2- (3-thienyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] propyl} carba 44.0 mg (80% yield) of the title compound were obtained from 66 mg (0.109 mmole) of mate.

¹ H NMR (CD ₃ OD) δ 8.41-8.40 (1H, m), 7.90-7.88 (1H, m), 7.55-7.52 (1H, m), 4.95-4.89 (2H, m), 3.88-3.79 (4H , m), 3.58-3.53 (1H, m), 3.50-3.45 (2H, m), 3.12-3.02 (2H, m), 2.74-2.68 (1H, m), 2.62-2.51 (3H, m), 2.40 -2.33 (2H, m)

Mass (m / e) 504 (M + 1)

Production Example  109: t-butyl {(1S) -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxo-3- [2- (2- Thienyl )-4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] propyl} Carbamate  synthesis

In the same manner as in Production Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(5R) -5-methyl-2-oxopiperidine-1 obtained from Production Example 51 -Yl] -butanoic acid 4-3.0 mg (0.137 mmole) and 2- (2-thienyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido obtained from Preparation Example 94 [ 3,4-d] pyrimidine hydrochloride 40.0 mg (0.124 mmole) was purified using separation to give 80.0 mg (yield 100%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 8.05-8.04 (1H, m), 7.52-7.51 (1H, m), 7.16-7.13 (1H, m), 5.89 (1H, brs), 4.87 (1H, s), 4.76 -4.69 (1H, m), 4.25-4.18 (1H, m), 3.91-3.88 (1H, m), 3.80-3.77 (1H, m), 3.67-3.51 (3H, m), 3.38-3.27 (1H, m), 3.11-2.99 (3H, m), 2.89-2.83 (1H, m), 2.56-2.28 (3H, m), 2.01-1.91 (1H, m), 1.85-1.81 (1H, m), 1.42- 1.41 (9H, m), 1.00 (3H, d, J = 6.8 Hz).

Mass (m / e) 582 (M + 1)

Example  62: (5R) -1-{(2S) -2-amino-4-oxo-4- [2- (2-thienyl) -4- (trifluoromethyl) -5,8-dihydropyrido Synthesis of [3,4-d] pyrimidin-7 (6H) -yl] butyl} -5-methylpiperidin-2-one

T-butyl {(1S) -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxo obtained in the same manner as in Example 22, from Production Example 109 -3- [2- (2-thienyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] propyl} carbox 58.6 mg (89% yield) of the title compound were obtained from 80.0 mg (0.138 mmole) of bamate.

¹ H NMR (CD ₃ OD) δ 8.04-8.03 (1H, m), 7.68-7.66 (1H, m), 7.21-7.18 (1H, m), 4.93-4.82 (2H, m), 3.93-3.86 (2H , m), 3.70-3.63 (1H, m), 3.56-3.44 (2H, m), 3.42-3.37 (1H, m), 3.10-3.00 (3H, m), 2.79-2.74 (1H, m), 2.66 -2.58 (1H, m), 2.45-2.32 (2H, m), 2.05-2.00 (1H, m), 1.85-1.81 (1H, m), 1.58-1.50 (1H, m), 1.05-1.03 (3H, m)

Mass (m / e) 482 (M + 1)

Production Example  110: t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3-oxo-3- [2- (2- Thienyl )-4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] propyl} Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidine-1 obtained from Preparation Example 57 -Yl] -butanoic acid 4-3.0 mg (0.137 mmole) and 2- (2-thienyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido obtained from Preparation Example 94 [ 3,4-d] pyrimidine hydrochloride 40.0 mg (0.124 mmole) was purified using separation to give 29.0 mg (yield 35%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 8.10-8.09 (1H, m), 7.57-7.55 (1H, m), 7.21-7.18 (1H, m), 5.83-5.81 (1H, m), 4.95-4.82 (1H, m), 4.81-4.72 (1H, m), 4.30-4.20 (1H, m), 3.95-3.93 (1H, m), 3.82-3.73 (3H, m), 3.63-3.62 (2H, m), 3.11- 3.04 (2H, m), 2.90-2.86 (1H, m), 2.66-2.57 (3H, m), 2.36-2.27 (2H, m), 1.46-1.45 (9H, m)

Mass (m / e) 604 (M + 1)

Example  63: 1-{(2S) -2-amino-4-oxo-4- [2- (2-thienyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4 Synthesis of -d] pyrimidin-7 (6H) -yl] butyl} -5,5-difluoropiperidin-2-one

In the same manner as in Example 22, t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3-oxo obtained from Preparation Example 110 -3- [2- (2-thienyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] propyl} carbox 29 mg (0.048 mmole) of barmate gave 20.3 mg (yield 84%) of the title compound.

¹ H NMR (CD ₃ OD) δ 8.06-8.05 (1H, m), 7.67-7.66 (1H, m), 7.21-7.19 (1H, m), 4.94-4.82 (2H, m), 3.94-3.78 (4H , m), 3.54-3.48 (3H, m), 3.11-3.02 (2H, m), 2.74-2.69 (1H, m), 2.62-2.56 (3H, m), 2.40-2.35 (2H, m)

Mass (m / e) 504 (M + 1)

Production Example  111: t-butyl {(1S) -3- [2- (2-furyl) -4- (trifluoromethyl) -5,8-dihydropyri Degree [3,4-d] pyrimidine -7 (6H) -yl] -1-{[(5R) -5- methyl -2- Oxopiperidine -1 day] methyl } 3- Oxov Lofil} Carbamate  synthesis

In the same manner as in Production Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(5R) -5-methyl-2-oxopiperidine-1 obtained from Production Example 51 -Yl] -butanoic acid 45.3 mg (0.144 mmole) and 2- (2-furyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3] from Preparation Example 95 , 4-d] pyrimidine hydrochloride was separated and purified using 40.0 mg (0.131 mmole) to obtain 70.0 mg (yield 86%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 7.68-7.65 (1H, m), 7.43-7.38 (1H, m), 6.61-6.59 (1H, m), 5.91-5.89 (1H, m), 4.98-4.87 (1H, m), 4.85-4.74 (1H, m), 4.20 (1H, brs), 3.94-3.89 (1H, m), 3.82-3.78 (1H, m), 3.62-3.48 (3H, m), 3.44-3.36 ( 1H, m), 3.08-3.01 (3H, m), 2.88-2.81 (1H, m), 2.58-2.28 (3H, m), 2.04 (1H, brs), 1.84-1.82 (1H, m), 1.42- 1.40 (9H, m), 1.00 (3H, d, J = 6.4 Hz).

Mass (m / e) 566 (M + 1-Boc)

Example  64: (5R) -1-{(2S) -2-amino-4- [2- (2-furyl) -4- (trifluoromethyl) -5,8-dich  Dropyrido [3,4-d] pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one

In the same manner as in Example 22, t-butyl {(1S) -3- [2- (2-furyl) -4- (trifluoromethyl) -5,8-dihydropyrido [obtained from Preparation Example 111 [ 3,4-d] pyrimidin-7 (6H) -yl] -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} 3-oxopropyl} carbamate 57.7 mg (93% yield) of the title compound were obtained from 70.0 mg (0.124 mmole).

¹ H NMR (CD ₃ OD) δ 7.81 (1H, m), 7.43-7.42 (1H, m), 6.70-6.68 (1H, m), 4.99-4.87 (2H, m), 3.98-3.83 (5H, m ), 3.59-3.55 (1H, m), 3.17-3.11 (2H, m), 3.04-2.98 (2H, m), 2.88-2.79 (1H, m), 2.48-2.41 (2H, m), 2.10-2.06 (1H, m), 1.90-1.85 (1H, m), 1.60-1.53 (1H, m), 1.06 (3H, d, J = 6.8 Hz).

Mass (m / e) 466 (M + 1)

Production Example  112: t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3- [2- (2- Furyl )-4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -3-oxopropyl} Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidine-1 obtained from Preparation Example 57 -Yl] -butanoic acid 48 mg (0.144 mmole) and 2- (2-furyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3 from Preparation Example 95] , 4-d] pyrimidine hydrochloride 40.0 mg (0.131 mmole) was purified by separation to give the title compound 75.0 mg (yield 89%).

¹ H NMR (CDCl ₃ ) δ 7.64 (1H, m), 7.40-7.38 (1H, m), 6.60-6.56 (1H, m), 5.82-5.79 (1H, m), 4.95-4.88 (1H, m) , 4.80-4.71 (1H, m), 4.20 (1H, brs), 3.92-3.85 (1H, m), 3.78-3.68 (3H, m), 3.60-3.50 (1H, m), 3.10-3.00 (2H, m), 2.85-2.78 (1H, m), 2.60-2.50 (3H, m), 2.30-2.20 (2H, m), 1.40 (9H, s)

Mass (m / e) 588 (M + 1)

Example  65: 1-{(2S) -2-amino-4- [2- (2- Furyl )-4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one

In the same manner as in Example 22, t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3- [obtained from Preparation Example 112. 2- (2-furyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] -3-oxopropyl} carba 48.9 mg (73% yield) of the title compound were obtained from 75 mg (0.128 mmole) of mate.

¹ H NMR (CD ₃ OD) δ 7.81-7.80 (1H, m), 7.43-7.42 (1H, m), 6.70-6.68 (1H, m), 4.98-4.88 (2H, m), 3.98-3.75 (6H , m), 3.61-3.50 (1H, m), 3.20-3.10 (1H, m) 3.07-2.99 (2H, m), 2.91-2.83 (1H, m), 2.69-2.62 (2H, m), 2.44- 2.34 (2H, m)

Mass (m / e) 488 (M + 1)

Production Example  113: t-butyl [(1S) -3- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydropyri Degree [3,4-d] pyrimidine -7 (6H) -yl] -1-{[(5R) -5- methyl -2- Oxopiperidine -1 day] methyl } 3- Oxov Lofil] Carbamate  synthesis

In the same manner as in Production Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(5R) -5-methyl-2-oxopiperidine-1 obtained from Production Example 51 -Yl] -butanoic acid 49.0 mg (0.155 mmole) and 2- (3-furyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3] from Preparation Example 96 , 4-d] pyrimidine hydrochloride was separated and purified using 43.0 mg (0.141 mmole) to obtain 80.0 mg (yield 91%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 8.25 (1H, s), 7.49-7.48 (1H, m), 7.04-7.03 (1H, m), 5.87-5.83 (1H, m), 4.85 (1H, s), 4.74 -4.67 (1H, m), 4.18-4.13 (1H, m), 3.89-3.87 (1H, m), 3.80-3.75 (1H, m), 3.62-3.47 (3H, m), 3.40-3.30 (1H, m), 3.07-2.95 (3H, m), 2.87-2.82 (1H, m), 2.52 -2.31 (3H, m), 1.93 (1H, brs), 1.80 (1H, brs), 1.41-1.39 (9H, m), 0.99 (3H, d, J = 6.9 Hz).

Mass (m / e) 566 (M + 1)

Example  66: (5R) -1-{(2S) -2-amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dich Dropyrido [3,4-d] pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one

In the same manner as in Example 22, t-butyl [(1S) -3- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydropyrido [ 3,4-d] pyrimidin-7 (6H) -yl] -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} 3-oxopropyl] carbamate 68.1 mg (95% yield) of the title compound were obtained from 80.0 mg (0.076 mmole).

¹ H NMR (CD ₃ OD) δ 8.53 (1H, s), 7.65-7.64 (1H, m), 7.08 (1H, s), 4.97-4.86 (2H, m), 3.96-3.83 (4H, m), 3.69-3.59 (1H, m), 3.43-3.37 (1H, m) 3.20-3.15 (4H, m), 2.88-2.75 (1H, m), 2.50-2.40 (2H, m), 2.06 (1H, brs) , 1.88-1.84 (1H, m), 1.60-1.51 (1H, m), 1.07 (3H, d, J = 6.4 Hz).

Mass (m / e) 466 (M + 1)

Production Example  114: t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3- [2- (3- Furyl )-4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -3-oxopropyl} Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidine-1 obtained from Preparation Example 57 -Yl] -butanoic acid 52 mg (0.155 mmole) and 2- (3-furyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3] obtained from Preparation Example 96 , 4-d] pyrimidine hydrochloride was separated and purified using 43.0 mg (0.141 mmole) to obtain 85.0 mg (yield 93%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 8.26 (1H, s), 7.49 (1H, s), 7.04-7.03 (1H, m), 5.77 (1H, brs), 4.84 (1H, s), 4.75-4.70 (1H , m), 4.20 (1H, brs), 3.88 (1H, brs), 3.75-3.68 (3H, m), 3.59-3.55 (2H, m), 3.06-2.99 (2H, m), 2.83-2.80 (1H , m), 2.58-2.53 (3H, m), 2.25 (2H, m), 1.41-1.40 (9H, m).

Mass (m / e) 588 (M + 1)

Example  67: 1-{(2S) -2-amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydropy Lido [3,4-d] pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one

In the same manner as in Example 22, t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3- [obtained from Preparation Example 114 2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] -3-oxopropyl} carba 68.8 mg (91% yield) of the title compound were obtained from 85 mg (0.145 mmole) of the mate.

¹ H NMR (CD ₃ OD) δ 8.36 (1H, s), 7.65-7.64 (1H, m), 7.09 (1H, s), 4.97-4.80 (2H, m), 3.98-3.79 (6H, m), 3.54-3.51 (1H, m), 3.15-3.01 (3H, m), 2.89-2.83 (1H, m), 2.65-2.61 (2H, m), 2.42-2.36 (2H, m)

Mass (m / e) 488 (M + 1)

Production Example  115: t-butyl {(1S) -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxo-3- [2- (1H-pyrrole- 2-day) -4- ( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] propyl} Carbamate  synthesis

In the same manner as in Production Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(5R) -5-methyl-2-oxopiperidine-1 obtained from Production Example 51 -Yl] -butanoic acid 2- (1H-pyrrol-2-yl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro from 27.3 mg (0.087 mmole) and preparation 98 Separation and purification using 24.0 mg (0.079 mmole) of pyrido [3,4-d] pyrimidine hydrochloride gave 43.0 mg (yield 88%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 9.55 (1H, brs), 7.20-7.18 (1H, m), 7.04 (1H, s), 6.39 (1H, s), 5.91-5.88 (1H, m), 4.86 (1H , s), 4.80-4.69 (1H, m), 4.23-4.17 (1H, m), 3.92-3.90 (1H, m), 3.81-3.79 (1H, m), 3.66-3.54 (1H, m), 3.66 -3.54 (2H, m), 3.41-3.38 (1H, m), 3.14-2.87 (4H, m), 2.57-2.37 (3H, m), 1.98 (1H, m), 1.85 (1H, m), 1.45 -1.44 (9H, m), 1.06-1.03 (3H, m)

Mass (m / e) 565 (M + 1)

Example  68: (5R) -1-{(2S) -2-amino-4-oxo-4- [2- (1H-pyrrol-2-yl) -4- (trifluorome Teal Synthesis of) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] butyl} -5-methylpiperidin-2-one

T-butyl {(1S) -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxo obtained in the same manner as in Example 22 -3- [2- (1H-pyrrol-2-yl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] Propyl} 35.2 mg (yield 86%) of the title compound were obtained from 43.0 mg (0.076 mmole) of carbamate.

¹ H NMR (CD ₃ OD) δ 7.10-7.09 (1H, m), 7.03-7.00 (1H, m), 6.28-6.26 (1H, m), 4.92-4.83 (2H, m), 3.96-3.93 (2H , m), 3.86-3.83 (2H, m), 3.77-3.66 (1H, m), 3.41-3.36 (1H, m), 3.23-2.83 (5H, m), 2.45-2.41 (2H, m), 2.06 (1H, brs), 1.86 (1H, m), 1.57-1.30 (1H, m), 1.05 (3H, d, J = 6.8 Hz).

Mass (m / e) 465 (M + 1)

Production Example  116: t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3-oxo-3- [2- (1H-pyrrole- 2-day) -4- ( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] propyl} Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidine-1 obtained from Preparation Example 57 -Yl] -butanoic acid, 20.0 mg (0.087 mmole) and 2- (1H-pyrrol-2-yl) -4- (trifluoromethyl) -5,6,7,8-tetrahydro from Preparation Example 98 Separation and purification using 24.0 mg (0.079 mmole) of pyrido [3,4-d] pyrimidine hydrochloride gave 37.0 mg (73% yield) of the title compound.

¹ H NMR (CDCl ₃ ) δ 9.55 (1H, brs), 7.20-7.18 (1H, m), 7.04 (1H, s), 6.40-6.38 (1H, m), 5.83-5.81 (1H, m), 4.86 (1H, s), 4.77-4.67 (1H, m), 4.27 (1H, brs), 3.94-3.90 (1H, m), 3.83-3.73 (3H, m), 3.64-3.62 (2H, m), 3.07 -3.00 (2H, m), 2.90-2.80 (1H, m), 2.65-2.58 (3H, m), 2.36-2.27 (2H, m), 1.46-1.45 (9H, s),

Mass (m / e) 587 (M + 1)

Example  69: 1-{(2S) -2-amino-4-oxo-4- [2- (1H-pyrrol-2-yl) -4- (trifluoromethyl) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] butyl} -5,5- Difluoropiperidine Synthesis of 2-one

In the same manner as in Example 22, t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3-oxo obtained from Preparation Example 116 -3- [2- (1H-pyrrol-2-yl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] 34.9 mg (99% yield) of the title compound were obtained from 37 mg (0.063 mmole) of propyl} carbamate.

¹ H NMR (CD ₃ OD) δ 7.10-7.08 (1H, m), 7.03-7.02 (1H, m), 6.28-6.26 (1H, m), 4.93-4.82 (2H, m), 3.97-3.74 (6H , m), 3.70-3.54 (1H, m), 3.09-2.87 (4H, m), 2.68-2.58 (2H, m), 2. 43-2.35 (2H, m)

Mass (m / e) 488 (M + 1)

Production Example  117: t-butyl {(1S) -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxo-3- [2-pyridin-3-yl -4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] propyl} Carbamate  synthesis

In the same manner as in Production Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(5R) -5-methyl-2-oxopiperidine-1 obtained from Production Example 51 -Yl] -butanoic acid 40.0 mg (0.127 mmole) and 2-pyridin-3-yl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3] from Preparation Example 97 , 4-d] pyrimidine hydrochloride 40.0 mg (0.126 mmole) was purified by separation to give 65.6 mg (yield 90%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 9.68 (1H, s), 8.78-8.76 (2H, m), 7.50-7.44 (1H, m), 5.94-5.92 (1H, m), 5.04-4.81 (2H, m) , 4.24 (1H, brs), 3.98-3.95 (1H, m), 3.87-3.84 (1H, m), 3.62-3.52 (2H, m), 3.44-3.39 (1H, m), 3.18-3.11 (3H, m), 2.89 (1H, m), 2.61-2.57 (1H, m), 2.45-2.35 (3H, m), 1.98 (1H, brs), 1.84 (1H, brs), 1.46-1.44 (9H, m) , 1.04 (3H, doublet, J = 8.0 Hz).

Mass (m / e) 577 (M + 1)

Example  70: (5R) -1-{(2S) -2-amino-4-oxo-4- [2-pyridin-3-yl-4- (trifluoromethyl) -5,8-dihydropyrido [ Synthesis of 3,4-d] pyrimidin-7 (6H) -yl] butyl} -5-methylpiperidin-2-one

T-butyl {(1S) -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxo, obtained in the same manner as in Example 22, from Production Example 117 -3- [2-pyridin-3-yl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] propyl} carba 55.6 mg (95% yield) of the title compound were obtained from 65.6 mg (0.114 mmole) of mate.

¹ H NMR (CD ₃ OD) δ 9.78 (1H, s), 9.62 (1H, d, 8.4 Hz), 9.07 (1H, d, 5.2 Hz), 8.35-8.32 (1H, m), 5.12-5.01 (2H , m), 4.03-3.95 (3H, m), 3.86-3.75 (1H, m), 3.70-3.59 (1H, m), 3.44-3.37 (1H, m), 3.28 (1H, brs), 3.19-2.96 (2H, m), 2.95-2.90 (2H, m), 2.45-2.42 (2H, m), 2.17 (1H, brs), 1.89-1.84 (1H, m), 1.59-1.54 (1H, m), 1.07 (3H, d, J = 6.4 Hz).

Mass (m / e) 477 (M + 1)

Production Example  118: t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3-oxo-3- [2-pyridin-3-yl -4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] propyl} Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidine-1 obtained from Preparation Example 57 -Yl] -butanoic acid 42.4 mg (0.127 mmole) and 2-pyridin-3-yl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3] from Preparation Example 97 , 4-d] pyrimidine hydrochloride was separated and purified using 40.0 mg (0.126 mmole) to obtain 71.0 mg (yield 93%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 9.67 (1H, s), 8.78-8.74 (2H, m), 7.50-7.41 (1H, m), 5.85-5.84 (1H, m), 5.03-4.92 (1H, m) , 4.91-4.78 (1H, m), 4.27-4.22 (1H, m), 3.98-3.95 (1H, m), 3.90-3.73 (3H, m), 3.67-3.57 (2H, m), 3.21-3.09 ( 2H, m), 2.91-2.87 (1H, m), 2.67-2.56 (3H, m), 2.35-2.30 (2H, m), 1.45 (9H, s)

Mass (m / e) 599 (M + 1)

Example  71: 1-{(2S) -2-amino-4-oxo-4- [2-pyridin-3-yl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d] Synthesis of pyrimidin-7 (6H) -yl] butyl} -5,5-difluoropiperidin-2-one

In the same manner as in Example 22, t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3-oxo obtained from Preparation Example 118 -3- [2-pyridin-3-yl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] propyl} carba 34.4 mg (64% yield) of the title compound were obtained from 65 mg (0.109 mmole) of mate.

¹ H NMR (CD ₃ OD) δ 9.78 (1H, s), 9.62 (1H, d, 8.0 Hz), 9.08 (1H, d, 4.0 Hz), 8.36-8.33 (1H, m), 5.12-5.01 (2H , m), 4.02-3.67 (6H, m), 3.62-3.51 (1H, m), 3.29 (1H, brs), 3.20-3.09 (2H, m), 3.03-2.95 (1H, m), 2.71-2.57 (2H, m), 2.43-2.37 (2H, m)

Mass (m / e) 499 (M + 1)

Production Example  119: (R)-(2-amino-1- methyl - Ethoxy )- Acetic acid  Synthesis of Ethyl Ester Hydrochloride

(One) (R)-(2-hydroxy-propyl)- Carbamic acid  Synthesis of t-butyl ester

723 mg (4.1 mmol) of the title compound were obtained in 61% yield using the experimental method of Preparation 6 (1) from (R) -1-amino-propan-2-ol (500 mg, 6.65 mmol).

NMR: ¹ H-NMR (CDCl ₃ ) δ 4.91 (1H, brs), 3.95-3.85 (1H, m), 3.30-3.22 (1H, m), 3.05-2.95 (1H, m), 1.43 (9H, s ), 1.16 (3H, d, J = 4 Hz)

Mass (EI) 176 (M ⁺ +1)

(2) (R)-(2-t- Butoxycarbonylamino -One- methyl - Ethoxy )- Acetic acid  Synthesis of Ethyl Ester

4.5 g (17.1 mmol) of the title compound were obtained from (R)-(2-hydroxy-propyl) -carbamic acid t-butyl ester (4.93 g, 28.1 mmol) using the experimental method of Preparation Example 10 (1). Obtained in% yield.

NMR: ¹ H-NMR (CDCl ₃ ) δ 5.39 (1H, s), 4.23 (2H, q, J = 8 Hz), 4.09 (1H, d, J = 16 Hz), 4.00 (1H, d, J = 16 Hz) , 3.60-3.35 (1H, m), 3.35-3.15 (1H, m), 3.10-3.04 (1H, m), 1.46 (9H, s), 1.31 (3H, t, J = 4 Hz), 1.16 (3H, d, J = 4 Hz)

Mass (EI) 262 (M ⁺ +1)

(3) (R)-(2-amino-1- methyl - Ethoxy )- Acetic acid  Synthesis of Ethyl Ester Hydrochloride

(R)-(2-t-butoxycarbonylamino-1-methyl-ethoxy) -acetic acid ethyl ester (4.5 g, 17.1 mmol) using the experimental method of Preparation Example 10 (4) 2.8 g (14 mmol) was obtained in 81% yield.

NMR: ¹ H-NMR (CDCl ₃ ) δ 8.55 (2H, s), 4.25 (2H, q, J = 8 Hz), 4.22 (1H, d, J = 20 Hz), 4.03 (1H, d, J = 20 Hz) , 3.80 to 3.70 (1H, m), 3.27 to 3.23 (1H, m), 3.03 to 2.97 (1H, m), 1.29 (3H, t, J = 4 Hz), 1.23 (3H, d, J = 4 Hz)

Mass (EI) 200 (M ⁺ +1)

Production Example  120: (S) -5-amino-4- methyl - Pentanoic acid methyl  Synthesis of Ester Hydrochloride

(One) (R) -3- A map -2- methyl - Propionic acid methyl  Synthesis of Ester

 From (R) -3-hydroxy-2-methyl-propionic acid methyl ester (5 g, 42.3 mmol) using the experimental method of Preparation Example 1 (4) (R) -3-methanesulfonyloxy-2 -Methyl-propionic acid methyl ester was obtained and then proceeded to the next step without further separation.

The resulting (R) -3-methanesulfonyloxy-2-methyl-propionic acid methyl ester was dissolved in 100 ml of dimethylformamide, followed by addition of sodium azide (8.2 g, 126 mmol) and stirring at 60 ° C. for 24 hours. After adding 400 ml of ethyl acetoacetate and washing with water, the organic layer was dried over magnesium sulfate. After distillation of the solvent under reduced pressure, 2 g (13.9 mmol) of the title compound were obtained in 32% yield by column chromatography.

NMR: 1 H-NMR (CDCl ₃ ) δ 3.71 (3H, s), 3.54 to 3.52 (1H, m), 3.40 to 3.30 (1H, m), 2.80 to 2.65 (1H, m), 1.20 (3H, d, J = 7.2 Hz)

Mass (EI) 144 (M ++ 1)

(2) (R) -3-t- Butoxycarbonylamino -2- methyl - Propionic acid methyl  Synthesis of Ester

Using (R) -3-azido-2-methyl-propionic acid methyl ester (2 g, 13.7 mmol) obtained in the step (1), 1.9 g of the title compound were obtained in the same manner as in Preparation Example 7 (3). 8.7 mmol) was obtained in 63% yield.

NMR: ¹ H-NMR (CDCl ₃ ) δ 4.92 (1H, brs), 3.70 (3H, s), 3.31-3.20 (2H, m), 2.70-2.55 (1H, m), 1.43 (9H, s), 1.15 (3H, d, J = 12 Hz)

Mass (EI) 218 (M ⁺ +1)

(3) (R)-(3-hydroxy-2- methyl -profile)- Carbamic acid  t- Butyl ester  synthesis

Using (R) -3-t-butoxycarbonylamino-2-methyl-propionic acid methyl ester (1.9 g, 8.7 mmol) obtained in the step (2), in the same manner as in Preparation Example 7 (4) 900 mg (4.7 mmol) of the title compound were obtained in 54% yield.

NMR: ¹ H-NMR (CDCl ₃ ) δ 4.78 (1H, brs), 3.55 to 3.50 (1H, m), 3.33 to 3.20 (2H, m), 3.05 to 2.98 (1H, m), 1.75 to 1.65 (1H , m), 1.46 (9H, s), 0.87 (3H, d, J = 12 Hz)

Mass (EI) 190 (M ⁺ +1)

(4) (R)-(2- methyl -3-oxo-propyl)- Carbamic acid  t- Butyl ester  synthesis

The title compound by the method of Preparation Example 6 (2) from (R)-(3-hydroxy-2-methyl-propyl) -carbamic acid t-butylester (900 mg, 4.7 mmol) obtained in the above step (3). 850 mg (4.5 mmol) was obtained in 95% yield.

Mass (EI) 188 (M ++ 1)

(5) (S) -5-t- Butoxycarbonylamino -4- methyl -2- Pentenoic acid Methyl ester  synthesis

From the (R)-(2-methyl-3-oxo-propyl) -carbamic acid t-butylester (850 mg, 4.5 mmol) obtained in the step (4), the title compound 1.19 was prepared by the method of Preparation Example 6 (3). g (4.4 mmol) was obtained in 97% yield.

NMR: 1 H-NMR (CDCl ₃ ) δ 6.84 (1H, dd, J = 15 Hz, 10 Hz), 5.84 (1H, d, J = 15 Hz), 4.55 (1H, brs), 3.72 (3H, s), 3.25- 3.15 (1H, m), 3.06-3.00 (1H, m), 2.54-2.47 (1H, m), 1.42 (9H, s), 1.03 (3H, d, J = 15 Hz)

Mass (EI) 244 (M ++ 1)

(6) (S) -5-t- Butoxycarbonylamino -4- methyl - Pentanoic acid Methyl ester  synthesis

Using (S) -5-t-butoxycarbonylamino-4-methyl-2-pentenoic acid methyl ester (1.09 g, 4.4 mmol) obtained in the step (5), the same procedure as in Preparation Example 7 (7) was carried out. The method gave 790 mg (3.2 mmol) of the title compound in 72% yield.

NMR: ¹ H-NMR (CDCl ₃ ) δ 4.90 (1H, brs), 3.67 (3H, s), 3.06 to 2.84 (2H, m), 2.43 to 2.27 (2H, m), 1.75 to 1.58 (2H, m ), 1.48-1.44 (1H, m), 1.44 (9H, s), 0.88 (3H, d, J = 6.8 Hz)

Mass (EI) 246 (M ⁺ +1)

(7) (S) -5-amino-4- methyl - Pentanoic acid methyl  Synthesis of Ester Hydrochloride

From (S) -5-t-butoxycarbonylamino-4-methyl-pentanoic acid methyl ester (790 mg, 3.2 mmol) obtained in the step (6), using the experimental method of Preparation Example 1 (4) 570 mg (3.1 mmol) of the title compound were obtained in 96% yield.

NMR: ¹ H-NMR (CD ₃ OD) δ 3.69 (3H, s), 2.94-2.89 (1H, m), 2.79-2.74 (1H, m), 2.52-2.36 (2H, m), 1.86-1.74 ( 2H, m), 1.54-1.47 (1H, m), 1.04 (3H, d, J = 7.2 Hz)

Mass (EI) 182 (M ⁺ +1)

Production Example  121: t-butyl (3S) -3-[(t-butoxycarbonyl) amino] -4-[(5S) -5-methyl-2-oxopiperidin-1-yl]- Butanoate  synthesis

In the same manner as in Production Example 42, (S) -5-amino-4 obtained from 3S-t-butoxycarbonylaminomino-4-oxo-butyric acid t-butylester obtained in Production Example 41 and Production Example 120 700 mg (3.85 mmol) of methyl-pentanoic acid methyl ester hydrochloride were used to obtain 770 mg (yield: 54%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 5.37 (1H, d, J = 7.0 Hz), 4.1-4.2 (1H, m), 3.8-3.9 (1H, m), 3.4-3.5 (1H, m), 3.0-3.1 (1H, m), 2.9 (1H, m), 2.3-2.6 (4H, m), 1.8-2.0 (2H, m), 1.45 (9H, s), 1.41 (9H, s), 1.0 (3H, d , J = 7.0 Hz)

Mass (m / e) 371 (M + 1)

Production Example  122: (3S) -3-[(t-butoxycarbonyl) amino] -4-[(5S) -5-methyl-2-oxopiperidin-1-yl]- Butanoic  synthesis

T-butyl (3S) -3-[(t-butoxycarbonyl) amino] -4-[(5S) -5-methyl-2-oxopiperi obtained in the same manner as in Production Example 43 770 mg (0.97 mmol) of din-1-yl] -butanoate were used to give 528 mg (two steps yield 81%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 5.6 (1H, m), 3.4-3.7 (3H, m), 3.0-3.1 (2H, m), 2.3-2.6 (4H, m), 1.8-2.0 (2H, m) , 1.41 (9H, s), 1.01 (3H, d, J = 6.5 Hz)

Mass (m / e) 315 (M + 1)

Production Example  123: methyl  [(2-amino-1- Methylethyl ) Thio ] Synthesis of Acetate

(One) t-butyl 3-[(2- Methoxy -2- Oxoethyl ) Thio ] Butanoate  synthesis

Methyl thioglycolate (0.8 ml, 8.9 mmol), piperidine (0.12 ml, 1.2 mmol) and t-butyl crotonate (2 g, 14 mmol) are stirred at room temperature for 12 hours and then distilled under reduced pressure. This solution was purified by column chromatography to give 2.05 g (8.2 mmol) of the title compound in 92% yield.

NMR: ¹ H-NMR (CDCl ₃ ) δ 3.74 (3H, s), 3.34 to 3.25 (2H, m), 2.57 (1H, dd, J = 6.0 Hz, 15.2 Hz), 2.37 (1H, dd, J = 8.4 Hz, 15.6 Hz), 1.84 (1H, dd, J = 2 Hz, 7.2 Hz), 1.45 (9H, s), 1.34 (3H, d, J = 6.8 Hz)

Mass (EI) 249 (M ⁺ +1)

(2) 3-[(2- Methoxy -2- Oxoethyl ) Thio ] Butanoic  Acid synthesis

The t-butyl 3-[(2-methoxy-2-oxoethyl) thio] butanoate (1.5 g, 6.0 mmol) obtained in the above step (1) was diluted with 10 ml of dichloromethane and 5 ml of trifluoroacetic acid at room temperature. After stirring for 6 hours, the mixture was distilled under reduced pressure. After adding 40 ml of ethyl acetoacetate and washing with water, the organic layer was dried over magnesium sulfate. After distilling off the solvent under reduced pressure, 1 g (5.1 mmol) of the title compound was obtained by using a column chromatography in 85% yield.

NMR: ¹ H-NMR (CDCl ₃ ) δ 3.75 (3H, s), 3.39 to 3.27 (3H, m), 2.73 (1H, dd, J = 6.4 Hz, 16 Hz), 2.55 (1H, dd, J = 7.6 Hz, 16 Hz), 1.39 (3H, d, J = 6.8 Hz)

Mass (EI) 193 (M ⁺ +1)

(3) methyl  [(2-amino-1- Methylethyl ) Thio ] Synthesis of Acetate

3-[(2-methoxy-2-oxoethyl) thio] butanoic acid (300 mg, 1.56 mmol) was dissolved in 12 ml of tetrahydrofuran and triethylamine (0.55 ml, 3.93 mmol) was added dropwise. Isobutyl chloroformate (0.4 ml, 3.08 mmol) was slowly added dropwise at 0 ° C. After stirring for 1 hour, a solution of sodium azide (1.8 g, 27.6 mmol) in 6 ml of water was added to the reaction solution and reacted for 30 minutes. After adding 50 ml of ethyl acetoacetate and washing with water, the organic layer was dried over magnesium sulfate. The solvent was distilled under reduced pressure and then proceeded to the next step without further separation.

This solution was dissolved in 5 ml of benzene, triethylamine (0.45 ml, 3.2 mmol) and 4-methoxy benzyl alcohol (0.39 ml, 3.12 mmol) were added, followed by stirring at 80 ° C. for 1 hour. The solvent was distilled off under reduced pressure, and then column chromatography was used to obtain methyl [(2- (4-methoxybenzylamino) -1-methylethyl) thio] acetate.

The compound obtained above was stirred at room temperature for 4 ml of dichloromethane and 2 ml of trifluoroacetic acid for 3 hours. After distillation of the solvent under reduced pressure, 250 mg (1.4 mmol) of the title compound were obtained by using a column chromatography in 89% yield.

NMR: ¹ H-NMR (CDCl ₃ ) δ 8.05 (2H, s), 3.76 (3H, s), 3.45-3.30 (2H, m), 3.27-3.20 (1H, m), 3.15-3.05 (1H, m ), 2.90-2.78 (1H, m), 1.40 (3H, d, J = 6.4 Hz)

Mass (EI) 164 (M ⁺ +1)

Production Example  124: t-butyl (3S) -3-[(t-butoxycarbonyl) amino] -4- (2-methyl-5-oxothiomorpholin-4-yl)- Butanoate  synthesis

In the same manner as in Production Example 42, 3S-t-butoxycarbonylamino-4-oxo-butyric acid t-butylester obtained in Production Example 41 and methyl [(2-amino-1-methyl] were obtained from Production Example 123. 200 mg (0.72 mmol) of ethyl) thio] acetate gave 210 mg (yield: 75%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 5.21 (1H, m), 3.9-4.0 (1H, m), 3.7-3.8 (3H, m), 3.2-3.3 (3H, m), 2.5-2.6 (2H, m) , 2.3-2.4 (1H, m), 1.44 (9H, s), 1.43 (9H, s), 1.2-1.3 (3H, m)

Mass (m / e) 389 (M + 1)

Production Example  125: (3S) -3-[(t-butoxycarbonyl) amino] -4- (2-methyl-5-oxothiomorpholin-4-yl)- Butanoic  synthesis

T-butyl (3S) -3-[(t-butoxycarbonyl) amino] -4- (2-methyl-5-oxothiomorpholin-4- obtained in the same manner as in Preparation Example 124 50 mg (two step yield 28%) of the title compound were obtained using 210 mg (0.54 mmol) of 1) -butanoate.

¹ H NMR (CDCl ₃ ) δ 5.61 (1H, br s), 3.5-3.8 (4H, m), 3.2-3.4 (3H, m), 2.5-2.7 (3H, m), 1.41 (9H, s), 1.29 (3H, doublet, J = 7.0 Hz)

Mass (m / e) 233 (M-tBoc)

Production Example  126: 2-methyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- d ]Pipe Midine  Synthesis of Hydrochloride

(One) t-butyl 2- methyl -4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4- d ] Pyrimidine -7 (6H) -car Leboxile Synthesis of sites

1.3 mL of sodium ethoxide (21% wt. Ethanol solution) was added at room temperature with 283 mg (3.0 mmol) of acetamidine hydrochloride dissolved in 5 mL of absolute ethanol. After stirring for 15 minutes, 590 mg (2.0 mmol) of t-butyl 3-oxo-4- (trifluoroacetyl) -piperidine-1-carboxylate obtained in Preparation Example 47 was diluted with 5 ml of anhydrous ethanol. It was added to the reaction solution. The reaction solution was warmed to 80 ° C. and stirred for 18 hours. After cooling to room temperature, ethanol was removed under reduced pressure, diluted with ethyl acetate and washed with brine. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, and the title compound was purified by column chromatography (10: 1 hexane: ethyl acetate) to give 98 mg (yield: 16%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 4.70 (2H, s), 3.72 (2H, t, J = 8.0 Hz), 3.00 (2H, br s), 1.50 (9H, s)

Mass (m / e) 318 (M + 1)

(2) 2- methyl -4-( Trifluoromethyl ) -5,6,7,8- Tetrahydropyrido [3,4-d] pyrimidine  Synthesis of Hydrochloride

T-butyl 2-methyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 (6H) -carboxylate 98 obtained in step (1) above Using mg (0.306 mmol), 70 mg (yield: 90%) of the title compound were obtained in the same manner as in Preparation Example 29.

¹ H NMR (CD ₃ OD) δ 4.45 (2H, s), 3.59 (2H, t, J = 7.0 Hz), 3.29 (2H, m), 2.72 (3H, s)

Mass (m / e) 218 (M + 1)

Production Example  127: 2,4-bis (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- d ]Pipe Midine  Synthesis of Hydrochloride

(One) t-butyl 2,4- Vis ( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -car Leboxile Synthesis of sites

800 mg (2.71 mmol) of t-butyl 3-oxo-4- (trifluoroacetyl) piperidine-1-carboxylate and 455 mg (4.06 mmol) of trifluoroacetamidine obtained in Preparation Example 25 were obtained. heated to 90 ° C. in ml ethanol and stirred for 15 h. After cooling to room temperature, ethanol was removed under reduced pressure, diluted with ethyl acetate, and washed with brine. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the title compound was purified by column chromatography (10: 1 hexane: ethyl acetate) to give 230 mg (yield: 23%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 4.67 (2H, s), 3.72 (2H, t, J = 8.0 Hz), 3.12 (2H, br s), 1.52 (9H, s)

Mass (m / e) 372 (M + 1)

(2) 2,4- Vis ( Trifluoromethyl ) -5,6,7,8- Tetrahydropyrido [3,4- d ] Pyrimidine  Synthesis of Hydrochloride

In the same manner as in Preparation Example 49, t-butyl 2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrimidine-7 ( 230 mg (0.62 mmol) of 6H) -carboxylate gave 184 mg (yield: 96%) of the title compound.

¹ H NMR (CD ₃ OD) δ 4.66 (2H, s), 3.69 (2H, t, J = 7.5 Hz), 3.42 (2H, t, J = 7.5 Hz)

Mass (m / e) 272 (M + 1)

Production Example  128: 2-ethyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- d ]Pipe  Midine  Synthesis of Hydrochloride

(One) Of propaneimidamide  synthesis

Trimethyl aluminum (9.07 ml, 18.14 mmol, 2.0 M toluene solution) was added dropwise to 40 ml of toluene with ammonium chloride (971 mg, 18.1 mmol) at room temperature. After stirring for 1.5 hours, propionitrile (1 g, 18.1 mmol) was added thereto, followed by heating at 85 ° C. for 9 hours. After the reaction, the solution was cooled, poured into 100 ml of chloroform containing 200 g of silica gel, filtered, washed with 100 ml of methanol, and distilled to obtain 1.01 g (14 mmol) of the compound in 77% yield.

NMR: ¹ H-NMR (CD ₃ OD) δ 2.46-2.44 (2H, m), 1.28-1.24 (3H, m)

Mass (EI) 73 (M ⁺ +1)

(2) t-butyl 2 Ethyl-4- ( Trifluoromethyl ) -5,8- Dihydropyrido [3,4- d ] Pyrimidine -7 (6H) -car Leboxile Synthesis of sites

In the same manner as in Preparation Example 48, 1.6 g (1.69 mmol) of t-butyl 3-oxo-4- (trifluoroacetyl) piperidine-1-carboxylate obtained in Preparation Example 47 and (1) 508 mg (7.04 mmol) of propaneimidamide obtained was used to obtain 160 mg (yield: 9%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 4.70 (2H, s), 3.72 (2H, t, J = 7.0 Hz), 3.0 (2H, m), 3.0 (2H, q, J = 7.5 Hz), 1.50 (9H, s), 1.37 (3H, t, J = 7.5 Hz)

Mass (m / e) 332 (M + 1)

(3) 2-ethyl-4- ( Trifluoromethyl ) -5,6,7,8- Tetrahydropyrido [3,4-d] pyrimidine  Synthesis of Hydrochloride

In the same manner as in Preparation Example 49, t-butyl 2-ethyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrimidine-7 obtained from step (2) 160 mg (0.62 mmol) of (6H) -carboxylate gave 60 mg (yield: 54%) of the title compound.

¹ H NMR (CD ₃ OD) δ 4.29 (2H, s), 3.42 (2H, t, J = 7.0 Hz), 3.12 (2H, br s), 2.98 (2H, q, J = 7.5 Hz), 1.32 ( 3H, t, J = 7.5 Hz)

Mass (m / e) 232 (M + 1)

Production Example  129: 2- (pentafluoroethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropy Lido [3,4-d] pyrimidine  Synthesis of Hydrochloride

(One) t-butyl 2 -( Pentafluoroethyl )-4-( Trifluoromethyl ) -5,8- Dehydropyri Degree[ 3,4-d] pyrimidine -7 (6H)- Carboxylate  synthesis

820 mg (2.78 mmol) of t-butyl 3-oxo-4- (trifluoroacetyl) piperidine-1-carboxylate obtained in Preparation Example 47 and 2,2,3,3,3-pentafluoropropane Dissolve 585 mg (3.61 mmol) of imidaded in 50 ml of isopropanol, add 10 μl (3% catalytic amount) of borontrifluoride diethyl lysate (BF ₃ OEt ₂ ), and then heat to 120 ° C. and stir for 17 hours. It was. After adding 1 to 2 drops of saturated aqueous sodium hydrogen carbonate solution, cooling to room temperature, isopropanol was removed under reduced pressure, and the resulting impure title compound was purified by column chromatography (10: 1 hexane: ethyl acetate) to give the title compound 690. mg (yield: 59%) were obtained.

¹ H NMR (CDCl ₃ ) δ 4.84 (2H, s), 3.77 (2H, t, J = 5.5 Hz), 3.11 (2H, br s), 1.50 (9H, s)

Mass (m / e) 422 (M + 1)

(2) 2-( Pentafluoroethyl )-4-( Trifluoromethyl ) -5,6,7,8- Tetrahydropyri Degree[ 3,4-d] pyrimidine  Synthesis of Hydrochloride

In the same manner as in Preparation Example 49, t-butyl 2- (pentafluoroethyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d obtained from step (1). ] 690 mg (0.08 mmol) of pyrimidine-7 (6H) -carboxylate gave 506 mg (yield: 96%) of the title compound.

¹ H NMR (CD ₃ OD) δ 4.65 (2H, s), 3.66 (2H, t, J = 6.0 Hz), 3.40 (2H, m)

Mass (m / e) 322 (M + 1)

Production Example  130: 2-isopropyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- d] pyrimidine  Synthesis of Hydrochloride

(One) 2- Of methyl propane imidamide  synthesis

Trimethyl aluminum (14.5 ml, 29 mmol, 2.0 M toluene solution) was added dropwise to 20 ml of toluene with ammonium chloride (1.55 g, 28.9 mmol) at room temperature. After stirring for 1.5 hours, isobutyronitrile (2 g, 28.9 mmol) was added thereto, followed by heating at 85 ° C. for 9 hours. After the reaction, the solution was cooled, poured into 200 ml of chloroform containing 500 g of silica gel, filtered, washed with 200 ml of methanol, and distilled to obtain 2.3 g (26.7 mmol) of the compound in 92% yield.

Mass (EI) 87 (M ⁺ +1)

(2) t-butyl  2-isopropyl-4- ( Trifluoromethyl ) -5,8- Dihydropyrido [3,4- d ]Pipe Midine-7 (6H)- Carboxylate  synthesis

In the same manner as in Preparation Example 61, 900 mg (3.05 mmol) of t-butyl 3-oxo-4- (trifluoroacetyl) piperidine-1-carboxylate obtained in Preparation Example 47 and in the step (1) 394 mg (4.58 mmol) of 2-methylpropaneimidamide obtained was used to give 174 mg (yield: 17%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 4.68 (2H, s), 3.70 (2H, t, J = 5.5 Hz), 3.21 (1H, m), 2.96 (2H, m), 1.50 (9H, s), 1.33 ( 6H, d, J = 7.0 Hz),

Mass (m / e) 346 (M + 1)

(3) 2-isopropyl-4- ( Trifluoromethyl ) -5,6,7,8- Tetrahydropyrido [3,4-d] pyrides Synthesis of Midine Hydrochloride

In the same manner as in Preparation Example 49, t-butyl 2-isopropyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrimidine- obtained from step (2) above. 174 mg (0.5 mmol) of 7 (6H) -carboxylate gave 80 mg (yield: 56%) of the title compound.

¹ H NMR (CD ₃ OD) δ 4.71 (2H, s), 3.59 (2H, t, J = 6.0 Hz), 3.22 (3H, m), 1.33 (6H, d, J = 7.0 Hz)

Mass (m / e) 246 (M + 1)

Production Example  131: 2-t-butyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- d ]Pipe Midine  Synthesis of Hydrochloride

(One) t-butyl 2 - t-butyl -4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -car Leboxile Synthesis of sites

In the same manner as in Preparation Example 48, 700 mg (2.37 mmol) of t-butyl 3-oxo-4- (trifluoroacetyl) piperidine-1-carboxylate obtained in Preparation Example 47 and 2,2-dimethylpropane 356 mg (3.56 mmol) of imidamide gave 29 mg (yield: 3.4%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 4.67 (2H, s), 3.71 (2H, t, J = 6.0 Hz), 2.96 (2H, m), 1.51 (9H, s), 1.39 (9H, s),

Mass (m / e) 360 (M + 1)

(2) 2-t-butyl-4- ( Trifluoromethyl ) -5,6,7,8- Tetrahydropyrido [3,4- d ] Pyrimidine  Synthesis of Hydrochloride

In the same manner as in Preparation Example 49, t-butyl 2-t-butyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrimidine obtained from step (1) 29 mg (0.08 mmol) of -7 (6H) -carboxylate gave 18 mg (yield: 90%) of the title compound.

¹ H NMR (CD ₃ OD) δ 4.45 (2H, s), 3.56 (2H, t, J = 6.0 Hz), 3.22 (2H, br t, J = 6.0 Hz), 1.39 (9H, s)

Mass (m / e) 260 (M + 1)

Production Example  132: t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3- [2-ethyl-4- ( Trifluoromethyl ) -5,8- Dihydropyrido [3,4- d ] Pyrimidine -7 (6H) -yl] -3- Oxov Lofil} Carbamate  synthesis

(3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidin-1-yl] -butanoic acid obtained from Preparation Example 57 ( 16 mg, 0.047 mmol) and 2-ethyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- d ] pyrimidine hydrochloride obtained in Preparation Example 128 were used. To obtain 21 mg (0.038 mmol, yield 82%) of the title compound in the same manner as in Preparation 45.

NMR: ¹ H-NMR (CDCl ₃ ) δ 5.79-5.77 (1H, brs), 4.89-4.78 (1H, m), 4.73-4.66 (1H, m), 4.25-4.15 (1H, m), 3.90-3.80 (1H, m), 3.74-3.71 (3H, m), 3,60-3.52 (2H, m), 3.05-2.97 (4H, m), 2.85-2.79 (1H, m), 2.60-2.50 (3H, m), 2.32-2.20 (2H, m), 1.41 (9H, s), 1.38-1.34 (3H, m)

Mass (EI) 550 (M ⁺ +1)

Example  72: 1-{(2S) -2-amino-4- [2-ethyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one hydrochloride

T-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3- [2-ethyl-4- (tri Fluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] -3-oxopropyl} carbamate (21 mg, 0.038 mmol) 13 mg (0.026 mmol, yield 68%) of the title compound were obtained in the same manner as the Example 22.

NMR: ¹ H-NMR (CD ₃ OD) δ 4.73-4.68 (2H, m), 3.80-3.67 (4H, m), 3.56-3.53 (2H, m), 3.38-3.36 (1H, m), 3.00- 2.97 (1H, m), 2.91-2.85 (3H, m), 2.69-2.45 (4H, m), 2.27-2.22 (2H, m), 1.27-1.13 (3H, m)

Mass (EI) 450 (M ⁺ +1)

Production Example  133: t-butyl (1S)-(3- [2-ethyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl ] -1-{[(2S) -2- methyl -5- Oxomorpholine -4-day] methyl } -3- Oxov Lofil) Carbamate  synthesis

(3S) -3-[(t-butoxycarbonyl) amino] -4-[(2S) -2-methyl-5-oxomorpholin-4-yl] -butanoic acid (15 obtained from Preparation Example 55 mg, 0.047 mmol) 2-ethyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- d ] pyrimidine hydrochloride (12 mg, 0.046 mM) to give 13 mg (0.024 mmol) of the title compound in 51% yield using the experimental method of Preparation 45.

NMR: ¹ H-NMR (CDCl ₃ ) δ 5.82-5.77 (1H, brs), 4.90-4.78 (1H, m), 4.75-4.66 (1H, m), 4.24-4.9 (3H, m), 3.93-3.83 (2H, m), 3.76-3.74 (1H, m), 3,69-3.62 (1H, m), 3.53-3.47 (1H, m), 3.37-3.30 (2H, m), 3.03-2.97 (4H, m), 2.88-2.81 (1H, m), 2.59-2.49 (1H, m), 1.41 (9H, s), 1.38-1.34 (3H, m), 1.27-1.24 (3H, m)

Mass (EI) 530 (M ⁺ +1)

Example  73: (6S) -4-{(2S) -2-amino-4- [2-ethyl-4- (trifluoromethyl) -5,8-dihydro Pyrido [3,4- d ] Pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -6-methylmorpholin-3-one hydrochloride

T-butyl (1S)-(3- [2-ethyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrimidine-7 (6H) obtained from Production Example 133. ) -Yl] -1-{[(2S) -2-methyl-5-oxomorpholin-4-yl] methyl} -3-oxopropyl) carbamate (13 mg, 0.024 mmol) from Example 22 Using the experimental method, 9 mg (0.019 mmol) of the title compound were obtained in 79% yield.

NMR: ¹ H-NMR (CD ₃ OD) δ δ 4.92-4.79 (2H, m), 4.21-4.14 (2H, m), 3.97-3.92 (2H, m), 3.87-3.83 (1H, m), 3 , 71 ~ 3.68 (1H, m), 3.56 ~ 3.53 (2H, m), 3.37 ~ 3.33 (2H, m), 3.10 ~ 2.97 (4H, m), 2.83 ~ 2.70 (1H, m), 2.69 ~ 2.61 ( 1H, m), 1.39-1.35 (3H, m), 1.26 (3H, d, J = 6.4 Hz)

Mass (EI) 430 (M ⁺ +1)

Production Example  134: t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3- [2-isopropyl-4- ( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -3-oxopropyl} Carbamate  synthesis

(3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidin-1-yl] -butanoic acid obtained from Preparation Example 57 ( 34 mg, 0.10 mmol) 2-isopropyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- d ] pyrimidine hydrochloride (Preparation example 130, 26 mg) , 0.092 mmol) to give 26 mg (0.046 mmol) of the title compound in 50% yield using the experimental method of Preparation 45.

Mass (EI) 564 (M ⁺ +1)

Example  74: 1-{(2S) -2-amino-4- [2-isopropyl-4- (trifluoromethyl) -5,8-dihydrate Ropyrido [3,4- d ] Pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one hydrochloride

T-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3- [2-isopropyl-4- (obtained from Preparation Example 134 Example from trifluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrimidin-7 (6H) -yl] -3-oxopropyl} carbamate (26 mg, 0.046 mmol) Using the experimental method of 22, 20 mg (0.040 mmol) of the title compound were obtained in 86% yield.

NMR: ¹ H-NMR (CD ₃ OD) δ 4.79-4.68 (2H, m), 3.83-3.66 (4H, m), 3.55-3.48 (2H, m), 3.38-3.36 (1H, m), 3.15- 3.07 (1H, m), 3.01-2.85 (2H, m), 2.69-2.64 (1H, m), 2.58-2.40 (3H, m), 2.29-2.19 (2H, m), 1.24-1.14 (6H, m) )

Mass (EI) 464 (M ⁺ +1)

Production Example  135: t-butyl (1S) -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3- [2-isoof Lofil -4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -3- Oxo profile} Carbamate  synthesis

(3S) -3-[(t-butoxycarbonyl) amino] -4-[(5R) -5-methyl-2-oxopiperidin-1-yl] -butanoic acid obtained from Preparation Example 51 ( 32.0 mg, 0.10 mmol) in 2-isopropyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- d ] pyrimidine hydrochloride (Preparation Example 130, 26 mg) , 0.092 mmol) to give 24 mg (0.044 mmol) of the title compound in a yield of 47% using the experimental method of Preparation 45.

Mass (EI) 542 (M ⁺ +1)

Example  75: 1-{(2S) -2-amino-4- [2-isopropyl-4- (trifluoromethyl) -5,8-dihydro Pyrido [3,4-d] pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one hydrochloride

T-butyl (1S) -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3- [2-isopropyl-4- (tri obtained from Preparation Example 135 Example 22 from fluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrimidin-7 (6H) -yl] -3-oxopropyl} carbamate (24 mg, 0.044 mmol) Using the experimental method of 18 mg (0.037 mmol) of the title compound was obtained in 84% yield.

NMR: ¹ H-NMR (CD ₃ OD) δ 4.86-4.78 (2H, m), 3.92-3.83 (2H, m), 3.67-3.62 (1H, m), 3.52-3.48 (2H, m), 3.41- 3.37 (1H, m), 3.25-3.20 (1H, m), 3.25-3.20 (2H, m), 3.10-3.00 (1H, m), 2.78-2.72 (1H, m), 2.65-2.58 (1H, m) ), 2.46-2.22 (2H, m), 2.05-2.00 (1H, m), 1.87-1.80 (1H, m), 1.58-1.47 (1H, m), 1.36-1.36 (6H, m), 1.04 (3H) , d, J = 6.8 Hz)

Mass (EI) 442 (M ⁺ +1)

Production Example  136: t-butyl (1S) -1-{[(2R) -2-methyl-5-oxomorpholin-4-yl] methyl} -3- [2-isopropyl-4- ( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -3- Oxov Lofil} Carbamate  synthesis

(3S) -3-[(t-butoxycarbonyl) amino] -4-[(2S) -2-methyl-5-oxomorpholin-4-yl] -butanoic acid (32.0) obtained from Preparation Example 55. mg, 0.10 mmol) to 2-isopropyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine hydrochloride (Preparation 130, 26 mg, 0.092 mmol) to give 24 mg (0.044 mmol) of the title compound in 47% yield using the experimental method of Preparation 45.

Mass (EI) 544 (M ⁺ +1)

Example  76: (6S) -4-{(2S) -2-amino-4- [2-isopropyl-4- (trifluoromethyl) -5,8-di Hydropyrido [3,4-d] pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -6-methylmorpholin-3-one hydrochloride

T-butyl (1S) -1-{[(2R) -2-methyl-5-oxomorpholin-4-yl] methyl} -3- [2-isopropyl-4- (trifluoro) obtained from Preparation Example 136 Rommethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] -3-oxopropyl} carbamate (24 mg, 0.044 mmol) from Example 22 Using the experimental method, 21 mg (0.043 mmol) of the title compound were obtained in 97% yield.

NMR: ¹ H-NMR (CD ₃ OD) δ 4.80-4.78 (2H, m), 4.20-4.08 (2H, m), 3.98-3.79 (3H, m), 3.59-3.52 (2H, m), 3.45- 3.32 (3H, m), 3.25-3.20 (1H, m), 3.09-2.94 (2H, m), 2.74-2.69 (1H, m), 2.61-2.53 (1H, m), 1.36-1.34 (6H, m) ), 1.25 (3H, d, J = 6.4 Hz)

Mass (EI) 444 (M ⁺ +1)

Production Example  137: t-butyl {(1S) -1-{[(2R) -2-methyl-5-oxomorpholin-4-yl] methyl} -3-oxo-3- [3- ( Trifluoromethyl ) -5,6- Dihydro [1,2,4] triazolo [4,3-a] pyrazin-7 (8H) -yl] propyl} Carbamate  synthesis

[1-formyl-3-oxo-3- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine obtained from Preparation Example 24 -7-yl) -propyl] -1S-carbamic acid t-butyl ester 300 mg (0.77 mmol) with ethyl [(1S) -2-amino-1-methylethoxy] acetate hydrochloride (Preparation 141, 152 mg , 0.77 mmol) and 325 mg (1.54 mmol) of sodium triacetoxyborohydride were reacted to give 150 mg of the title compound (yield: 40%).

¹ H NMR (CDCl ₃ ) δ 5.8-6.0 (1H, m), 4.8-5.1 (2H, m), 3.8-4.3 (9H, m), 3.6 (1H, m), 3.2-3.4 (2H, m) , 2.7-2.9 (1H, m), 2.4-2.6 (1H, m), 1.40 (9H, s), 1.20 (3H, br d, J = 6.0 Hz)

Mass (m / e) 491 (M + 1)

Example  77: (6R) -4-{(2S) -2-amino-4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4 Synthesis of, 3-a] pyrazin-7 (8H) -yl] butyl} -6-methylmorpholin-3-one

T-butyl {(1S) -1-{[(2R) -2-methyl-5-oxomorpholin-4-yl] methyl} -3-oxo- obtained in the same manner as in Example 22 150 mg of 3- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazin-7 (8H) -yl] propyl} carbamate Was reacted with ethyl acetate / hydrochloric acid solution to give 80 mg of the title compound (yield: 67%).

¹ H NMR (CD ₃ OD) δ 4.9-5.1 (2H, m), 4.1-4.4 (4H, m), 3.8-4.1 (4H, m), 3.3-3.5 (2H, m), 2.7-3.0 (2H , m), 1.22 (3H, m)

Mass (m / e) 391 (M + 1)

Production Example  138: t-butyl {(1S) -1-{[(2S) -2-methyl-5-oxomorpholin-4-yl] methyl} -3-oxo-3- [3- ( Trifluoromethyl ) -5,6- Dihydro [1,2,4] triazolo [4,3-a] pyrazin-7 (8H) -yl] propyl} Carbamate  synthesis

115 mg (3S) -3-[(t-butoxycarbonyl) amino] -4-[(2S) -2-methyl-5-oxomorpholin-4-yl] -butanoic acid from Preparation Example 55 (0.36 mmol) and 3- (trifluoromethyl) -5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine 70 synthesized with reference to WO 03/004498 mg (0.36 mmol) was used to give 100 mg of the title compound (yield: 56%).

¹ H NMR (CDCl ₃ ) δ 5.87 (1H, m), 4.8-5.1 (2H, m), 3.9-4.3 (7H, m), 3.8-3.9 (1H, m), 3.6-3.7 (1H, m) , 3.2-3.4 (3H, m), 2.6-2.9 (2H, m), 1.39 (9H, s), 0.9 (3H, br d, J = 7.0 Hz)

Mass (m / e) 491 (M + 1)

Example  78: (6S) -4-{(2S) -2-amino-4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4 Synthesis of, 3-a] pyrazin-7 (8H) -yl] butyl} -6-methylmorpholin-3-one

T-butyl {(1S) -1-{[(2S) -2-methyl-5-oxomorpholin-4-yl] methyl} -3-oxo- obtained from Production Example 138 in the same manner as in Example 22 3- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazin-7 (8H) -yl] propyl} carbamate 100 mg Was reacted with ethyl acetate / hydrochloric acid solution to give 37 mg of the title compound (yield: 47%).

¹ H NMR (CD ₃ OD) δ 4.9-5.1 (2H, m), 4.0-4.4 (7H, m), 3.8-4.0 (2H, m), 3.6-3.7 (2H, m), 3.3-3.4 (2H , m), 2.8-3.0 (2H, m), 1.3 (3H, d, J = 6.5 Hz)

Mass (m / e) 391 (M + 1)

Production Example  139: t-butyl {(1S) -1-{[(5S) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxo-3- [3- ( Trifluoromethyl ) -5,6- Dihydro [1,2,4] triazolo [4,3-a] pyrazin-7 (8H) -yl] propyl} Carbamate  synthesis

(3S) -3-[(t-butoxycarbonyl) amino] -4-[(5S) -5-methyl-2-oxopiperidine- obtained from Production Example 122 in the same manner as in Production Example 45 3- (trifluoromethyl) -5,6-dihydro-8H- [1,2,4] tria synthesized with 50 mg (0.16 mmol) of 1-yl] -butanoic acid and WO 03/004498 31 mg (0.16 mmol) of zolo [4,3-a] pyrazine gave 30 mg of the title compound (yield: 38%).

¹ H NMR (CDCl ₃ ) δ 5.97 (1H, m), 4.8-5.1 (2H, m), 3.9-4.3 (6H, m), 3.3-3.7 (3H, m), 2.7-3.0 (2H, m) , 2.2-2.5 (3H, m), 1.7-2.0 (2H, m), 1.39 (9H, s), 0.99 (3H, br d, J = 6.5 Hz)

Mass (m / e) 489 (M + 1)

Example  79: (5S) -1-{(2S) -2-amino-4-oxo-4- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4 Synthesis of, 3-a] pyrazin-7 (8H) -yl] butyl} -5-methylpiperidin-2-one

T-butyl {(1S) -1-{[(5S) -5-methyl-2-oxopiperidin-1-yl] methyl} -3- obtained in the same manner as in Example 22, from Production Example 139 Oxo-3- [3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazin-7 (8H) -yl] propyl} carbamate Reaction of 30 mg gave 11.6 mg of the title compound (yield: 49%).

¹ H NMR (CD ₃ OD) δ 4.9-5.1 (2H, m), 4.0-4.4 (4H, m), 3.7-3.9 (2H, m), 3.3-3.5 (2H, m), 2.7-3.1 (3H , m), 2.37 (2H, br), 1.9-2.1 (1H, br s), 1.8-1.9 (1H, m), 1.4-1.6 (1H, m), 1.03 (3H, m)

Mass (m / e) 389 (M + 1)

Production Example  140: t-butyl [(1S) -3- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] -1-{[(5S) -5- methyl -2- Oxopiperidine -1 day] methyl } -3- Oxo profile] Carbamate  synthesis

(3S) -3-[(t-butoxycarbonyl) amino] -4-[(5S) -5-methyl-2-oxopiperidine- obtained from Production Example 122 in the same manner as in Production Example 45 26 mg (0.08 mmol) of 1-yl] -butanoic acid and 2,4-bis (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine hydrochloride 25 mg (Preparation 127, 0.08 mmol) were used to give 3 mg of the title compound (yield: 6.4%).

¹ H NMR (CDCl ₃ ) δ 5.94 (1H, m), 4.8-5.1 (2H, m), 4.1-4.2 (2H, m), 3.7-3.8 (2H, m), 3.5-3.6 (1H, m) , 3.3-3.5 (2H, m), 3.1-3.3 (2H, m), 2.8-3.0 (1H, m), 2.3-2.5 (3H, m), 1.8-2.0 (2H, m), 1.6-1.7 ( 1H, m), 1.40 (9H, s), 1.01 (3H, d, J = 7 Hz)

Mass (m / e) 568 (M + 1)

Example  80: (5S) -1-{(2S) -2-amino-4- [2,4- Vis ( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one

T-butyl [(1S) -3- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4- obtained from Production Example 140 in the same manner as in Example 22 d] pyrimidin-7 (6H) -yl] -1-{[(5S) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxopropyl] carbamate 3.0 mg Reaction gave 2.3 mg of the title compound (yield: 93%).

¹ H NMR (CD ₃ OD) δ 4.8-5.0 (2H, m), 3.8-4.0 (1H, m), 3.3-3.7 (5H, m), 3.0-3.2 (3H, m), 2.5-2.7 (2H , m), 2.3-2.4 (2H, m), 1.8-2.0 (2H, m), 1.4-1.5 (1H, m), 1.02 (3H, m)

Mass (m / e) 468 (M + 1)

Production Example  141: t-butyl {(1S) -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3- [2-methyl-4- ( Trifluoromethyl ) -5,8- Dihydropyrido [3,4- d ] Pyrimidine -7 (6H) -yl] -3- Oxopro Phil} Carbamate  synthesis

(3S) -3-[(t-butoxycarbonyl) amino] -4-[(5R) -5-methyl-2-oxopiperidin-1-yl] -butanoic acid 131 obtained from Preparation Example 51 106 mg (0.418) of 2-methyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- d ] pyrimidine hydrochloride obtained from mg (0.418 mmol) and Preparation Example 126 mmol) to give 137 mg (yield: 64%) of the title compound in the same manner as in Preparation 45.

¹ H NMR (CDCl ₃ ) δ 5.88 (1H, brs), 4.89-4.78 (1H, m), 4.76-4.64 (1H, m), 4.17-4.10 (1H, m), 3.78-3.73 (1H, m) , 3.62-3.48 (2H, m), 3.39-3.33 (1H, m), 3.11-2.96 (3H, m), 2.84-2.79 (1H, m), 2.76 (3H, s), 2.60-2.20 (3H, m), 1.96-1.93 (1H, m), 1.84-1.81 (1H, m), 1.49-1.42 (1H, m), 1.40 (9H, s), 1.00 (3H, d, J = 6.8 Hz).

Mass (m / e) 414 (M + 1-Boc)

Example  81: (5R) -1-{(2S) -2-amino-4- [2-methyl-4- (trifluoromethyl) -5,8-dihydropy Lido [3,4-d] pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one

T-butyl {(1S) -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3- [2-methyl-4- (tri obtained from Preparation Example 141 Example using 137 mg (0.267 mmol) of fluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrimidin-7 (6H) -yl] -3-oxopropyl} carbamate In the same manner as in 1, 99 mg (yield: 83%) of the title compound were obtained.

¹ H NMR (CD ₃ OD) δ 4.89-4.79 (2H, m), 3.94-3.91 (1H, m), 3.89-3.81 (1H, m), 3.77-3.73 (1H, m), 3.67-3.61 (1H , m), 3.56-3.52 (1H, m), 3.41-3.52 (1H, m), 3.14-3.08 (2H, m), 3.02-2.98 (1H, m), 2.90-2.66 (2H, m), 2.73 (3H, s), 2.50-2.33 (2H, m), 2.05-2.00 (1H, m), 1.89-1.84 (1H, m), 1.59-1.49 (1H, m), 1.07 (3H, d, J = 6.8 Hz).

Mass (m / e) 414 (M + 1)

Production Example  142: t-butyl {(1S) -3- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] -1-{[(5R) -5- methyl -2- Oxopiperidine -1 day] methyl } -3- Oxo profile} Carbamate  synthesis

In the same manner as in Production Example 42, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(5R) -5-methyl-2-oxopiperidine-1 obtained from Production Example 51 64 mg (0.205 mmol) of -yl] -butanoic acid and 63 mg of 2,4-bis (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- d ] pyrimidine hydrochloride (Preparation 127, 0.205 mmol) were obtained to give 28 mg of the title compound (yield: 24%).

¹ H NMR (CDCl ₃ ) δ 5.96-5.91 (1H, m), 5.08-4.88 (1H, m), 4.90-4.67 (1H, m), 4.15-4.10 (1H, m), 4.03-3.80 (2H, m), 3.62-3.57 (1H, m), 3.53-3.44 (1H, m), 3.40-3.31 (1H, m), 3.27-3.01 (3H, m), 2.90-2.79 (1H, m), 2.57- 2.17 (4H, m), 1.94 (1H, brs), 1.81 (1H, brs), 1.42-1.40 (9H, m), 1.01 (3H, d, J = 6.4 Hz).

Mass (m / e) 468 (M + 1-Boc)

Example  82: (5R) -1-{(2S) -2-amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydropy Lido [3,4- d ] Pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one

T-butyl {(1S) -3- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4- d obtained from Production Example 142 in the same manner as in Example 1 ] Pyrimidin-7 (6H) -yl] -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxopropyl} carbamate 47 mg (0.083) mmol) gave 33 mg (yield: 80%) of the title compound.

¹ H NMR (CD ₃ OD) δ 5.05-4.89 (2H, m), 3.98-3.90 (2H, m), 3.73-3.70 (1H, m), 3.64-3.49 (2H, m), 3.42-3.30 (3H , m), 3.24 (1H, brs), 3.13-3.05 (2H, m), 2.88-2.81 (1H, m), 2.75-2.62 (1H, m), 2.49-2.36 (2H, m), 2.03 (1H , brs), 1.86 (1H, brs), 1.60-1.48 (1H, m), 1.06 (3H, d, J = 6.4 Hz).

Mass (m / e) 468 (M + 1)

Production Example  143: t-butyl {(1S) -3- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] -1-[(5,5- Difluoro -2- Oxopiperidine -1 day) methyl ] -3- jade Small profile} Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidine-1 obtained from Preparation Example 57 -Yl] -butanoic acid 46.4 mg (0.138 mmol) and 2,4-bis (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- d ] pyrimidine hydrochloride 42.5 mg (Preparation 127, 0.138 mmol) were obtained to give 42 mg of the title compound (yield: 51%).

¹ H NMR (CDCl ₃ ) δ 5.83-5.79 (1H, m), 5.05-4.91 (1H, m), 4.89-4.78 (1H, m), 4.17 (1H, brs), 4.00-3.58 (5H, m) , 3.52-3.48 (1H, m), 3.20-3.12 (2H, m), 2.85-2.78 (1H, m), 2.59-2.48 (3H, m), 2.29-2.25 (2H, m), 1.48-1.40 ( 9H, m)

Mass (m / e) 490 (M + 1-Boc)

Example  83: 1-{(2S) -2-amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] Pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one

T-butyl {(1S) -3- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4- d obtained from Production Example 143 in the same manner as in Example 1 ] Pyrimidin-7 (6H) -yl] -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3-oxopropyl} carbamate 42 mg (0.071) mmol) gave 21 mg (yield: 56%) of the title compound.

¹ H NMR (CD ₃ OD) δ 5.05-4.92 (2H, m), 3.98-3.91 (2H, m), 3.85-3.79 (2H, m), 3.70-3.59 (2H, m), 3.54-3.48 (1H , m), 3.36-3.33 (2H, m), 3.24 (1H, brs), 3.14 (1H, brs), 2.83-2.76 (1H, m), 2.72-2.53 (3H, m), 2.43-2.34 (2H , m)

Mass (m / e) 490 (M + 1)

Production Example  144: t-butyl {(1S) -3- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] Pyrimidin-7 (6H) -yl] -1-{[(2S) -2- methyl -5- Oxomorpholine -4-day] methyl } -3- Oxov Lofil} Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(2S) -2-methyl-5-oxomorpholine-4- obtained from Preparation Example 55 43.7 mg (0.138 mmol) of 1 ] -butanoic acid and 42.5 mg of 2,4-bis (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- d ] pyrimidine hydrochloride Preparation 127, 0.138 mmol) was reacted to give 14 mg of the title compound (yield: 17%).

¹ H NMR (CDCl ₃ ) δ 5.85-5.83 (1H, m), 5.09-4.92 (1H, m), 4.95-4.78 (1H, m), 4.23-4.08 (3H, m), 4.04-3.76 (3H, m), 3.73-3.66 (1H, m), 3.46-3.38 (1H, m), 3.36-3.21 (2H, m), 3.18-3.10 (2H, m), 2.96-2.81 (1H, m), 2.61- 2.50 (1 H, m), 1.43-1.41 (9 H, m), 1.28-1.24 (3 H, m).

Mass (m / e) 470 (M + 1-Boc)

Example  84: (6S) -4-{(2S) -2-amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine- Synthesis of 7 (6H) -yl] -4-oxobutyl} -6-methylmorpholin-3-one

T-butyl {(1S) -3- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4-d obtained from Production Example 144 in the same manner as in Example 1 ] Pyrimidin-7 (6H) -yl] -1-{[(2S) -2-methyl-5-oxomorpholin-4-yl] methyl} -3-oxopropyl} carbamate 14 mg (0.023 mmol) 6.9 mg (yield: 59%) of the title compound were obtained.

¹ H NMR (CD ₃ OD) δ 4.89-4.80 (2H, m), 4.16-4.06 (3H, m), 3.92-3.85 (4H, m), 3.55-3.50 (2H, m), 3.34-3.30 (1H , m), 3.19 (1H, brs), 3.09 (1H, brs), 2.70-2.61 (1H, m), 2.59-2.53 (1H, m), 1.23-1.20 (3H, m)

Mass (m / e) 470 (M + 1)

Production Example  145: t-butyl  {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3- [2-methyl-4- ( Trifluoromethyl ) -5,8- Dihydropyrido [3,4- d ] Pyrimidine -7 (6H) -yl] -3- Oxov Lofil} Carbamate  synthesis

(3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidin-1-yl] -butanoic acid 55.3 obtained from Preparation Example 57 mg (0.164 mmol) and 41.7 mg (0.164) of 2-methyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- d ] pyrimidine hydrochloride from Preparation Example 126 mmol) to give 51.6 mg of the title compound in the same manner as in Preparation 45 (yield: 59%).

¹ H NMR (CDCl ₃ ) δ 5.79-5.76 (1H, m), 4.84-4.78 (1H, m), 4.69-4.61 (1H, m), 4.18 (1H, brs), 3.88-3.80 (1H, m) , 3.76-3.65 (3H, m), 3.60-3.52 (2H, m), 3.02-2.95 (3H, m), 2.82-2.73 (4H, m), 2.57-2.49 (3H, m), 2.27-2.20 ( 1H, m), 1.38-1.37 (9H, m)

Mass (m / e) 436 (M + 1-Boc)

Example  85: 1-{(2S) -2-amino-4- [2-methyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] Pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one

T-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3- [2-methyl-4- (tri obtained from Preparation Example 145 Example using 51.6 mg (0.119 mmol) of fluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrimidin-7 (6H) -yl] -3-oxopropyl} carbamate 43 mg (yield: 78%) of the title compound were obtained in the same manner as the 22.

¹ H NMR (CD ₃ OD) δ 4.83-4.77 (2H, m), 3.89-3.74 (4H, m), 3.68-3.60 (3H, m), 3.47-3.43 (1H, m), 3.30 (3H, s ), 3.06 (1H, brs), 2.97 (1H, brs), 2.67-2.54 (2H, m), 2.37-2.30 (3H, m)

Mass (m / e) 436 (M + 1)

Production Example  146: t-butyl {(1S) -1-{[(2S) -2-methyl-5-oxomorpholin-4-yl] methyl} -3- [2-methyl-4- ( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -3- Oxopropyl } Synthesis of Carbamate

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(2S) -2-methyl-5-oxomorpholine-4- obtained from Preparation Example 55 62.4 mg (0.197 mmol) of 1] -butanoic acid and 50 mg of 2-methyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine hydrochloride (Preparation Example 128, 0.197 mmol) was obtained to give 39.8 mg of the title compound (yield: 39%).

¹ H NMR (CDCl ₃ ) δ 5.82-5.77 (1H, m), 4.90-4.78 (1H, m), 4.75-4.63 (1H, m), 4.29-4.09 (2H, m), 3.95-3.82 (2H, m), 3.80 (1H, brs), 3.76-3.62 (1H, m), 3.53-3.45 (1H, m), 3.41-3.29 (2H, m), 3.10-2.96 (2H, m), 2.89-2.80 ( 1H, m), 2.76 (3H, s), 2.60-2.49 (1H, m), 1.43-1.42 (9H, m), 1.28-1.24 (3H, m).

Mass (m / e) 470 (M + 1-Boc)

Example  86: (6S) -4-{(2S) -2-amino-4- [2-methyl-4- (trifluoromethyl) -5,8-dihydro Pyrido [3,4- d ] Pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -6-methylmorpholin-3-one

In the same manner as in Example 22, t-butyl {(1S) -1-{[(2S) -2-methyl-5-oxomorpholin-4-yl] methyl} -3- [2 obtained from Production Example 146. 39.8 mg (0.077) of methyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrimidin-7 (6H) -yl] -3-oxopropyl} carbamate mmol) gave 26.5 mg (yield: 76%) of the title compound.

¹ H NMR (CD ₃ OD) δ 4.83-4.77 (2H, m), 4.18-4.07 (3H, m), 3.95-3.88 (2H, m), 3.83-3.81 (1H, m), 3.58-3.52 (2H , m), 3.38-3.29 (1H, m), 3.07 (1H, brs), 2.97 (1H, brs), 2.81-2.76 (1H, m), 2.70-2.69 (3H, m), 2.67-2.60 (1H m), 1.23 (3H, doublet, J = 6.1 Hz).

Mass (m / e) 416 (M + 1)

Production Example  147: t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3-oxo-3- [4- ( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine Synthesis of -7 (6H) -yl] propyl} carbamate

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidine-1 obtained from Preparation Example 57 -Yl] -butanoic acid 16 mg (0.067 mmol) and 22.5 mg of 4-trifluoromethyl-5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine hydrochloride (Preparation 49, 0.067 mmol) to give 16.4 mg of the title compound (yield 47%).

¹ H NMR (CDCl ₃ ) δ 9.16-9.15 (1H, m), 5.81-5.79 (1H, m), 4.95-4.84 (1H, m), 4.81-4.70 (1H, m), 4.22-4.13 (1H, m), 3.92-3.89 (1H, m), 3.79-3.69 (3H, m), 3.65-3.52 (2H, m), 3.15-3.10 (1H, m), 3.06 (1H, brs), 2.86-2.79 ( 1H, m), 2.62-2.52 (3H, m), 2.36-2.22 (2H, m), 1.42-1.41 (9H, m).

Mass (m / e) 422 (M + 1-BOC)

Example  87: 1-{(2S) -2-amino-4-oxo-4- [4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] Pyrimidine Synthesis of -7 (6H) -yl] butyl} -5,5-difluoropiperidin-2-one

In the same manner as in Example 22, t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3-oxo obtained from Preparation Example 147 From 16.4 mg (0.032 mmol) of 3--3- [4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrimidin-7 (6H) -yl] propyl} carbamate 9.7 mg (yield 67%) of the title compound were obtained.

¹ H NMR (CD ₃ OD) δ 9.03-9.02 (1H, m), 4.84-4.73 (2H, m), 3.84-3.66 (3H, m), 3.62-3.48 (3H, m), 3.43-3.35 (1H , m), 3.06-3.03 (1H, m), 2.95 (1H, brs), 2.75-2.57 (2H, m), 2.55-2.42 (2H, m), 2.31-2.20 (2H, m)

Mass (m / e) 422 (M + 1)

Production Example  148: t-butyl {(1S) -1-{[(2S) -2-methyl-5-oxomorpholin-4-yl] methyl} -3-oxo-3- [4- ( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine Synthesis of -7 (6H) -yl] propyl} carbamate

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(2S) -2-methyl-5-oxomorpholine-4- obtained from Preparation Example 55 21 mg (0.067 mmol) of Japanese] -butanoic acid and 16 mg of 4-trifluoromethyl-5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine hydrochloride (Preparation 49, 0.067) mmol) was reacted to give 16.4 mg of the title compound (yield 47%).

¹ H NMR (CDCl ₃ ) δ 9.15-9.14 (1H, m), 5.83-5.78 (1H, m), 4.96-4.84 (1H, m), 4.82-4.70 (1H, m), 4.29-4.08 (3H, m), 3.93-3.83 (2H, m), 3.77 (1H, brs), 3.70-3.63 (1H, m), 3.40-3.31 (1H, m), 3.51-3.45 (1H, m), 3.40-3.31 ( 2H, m), 3.20-3.00 (2H, m), 2.61-2.50 (1H, m), 1.42-1.42 (9H, m), 1.28-1.26 (3H, m).

Mass (m / e) 402 (M + 1-BOC)

Example  88: (6S) -4-{(2S) -2-amino-4-oxo-4- [4- (trifluoromethyl) -5,8-dihydro Pyrido [3,4- d ] Pyrimidine Synthesis of -7 (6H) -yl] butyl} -6-methylmorpholin-3-one

T-butyl {(1S) -1-{[(2S) -2-methyl-5-oxomorpholin-4-yl] methyl} -3-oxo- obtained in Preparation 148 in the same manner as in Example 22 From 10.5 mg (0.021 mmol) of 3- [4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrimidin-7 (6H) -yl] propyl} carbamate 6.7 mg (yield 73%) of compound were obtained.

¹ H NMR (CDCl ₃ ) δ 9.11-9.10 (1H, m), 4.88-4.81 (2H, m), 4.17-4.08 (3H, m), 3.95-3.86 (2H, m), 3.85-3.81 (1H, m), 3.68-3.64 (1H, m), 3.53-3.50 (2H, m), 3.32-3.29 (1H, m), 3.12 (1H, brs), 3.02 (1H, brs), 2.80-2.75 (1H, m), 2.66-2.58 (1H, m), 1.23 (3H, d, J = 6.1 Hz).

Mass (m / e) 402 (M + 1)

Production Example  149: t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3-oxo-3- [3- ( Pentafluoroethyl ) -5,6- Dihydro [1,2,4] triazolo [4,3-a] pyrazin-7 (8H) -yl] propyl} Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidine-1 obtained from Preparation Example 57 43 mg (0.178 mmol) of -yl] -butanoic acid and 3- (pentafluoroethyl) -5,6-dihydro [1,2,4] triazolo obtained with reference to JMC 2005, 48 , p141-151. 43 mg (0.178 mmol) of [4,3-a] pyrazine were reacted to give 63 mg of the title compound (yield: 63%).

¹ H NMR (CDCl ₃ ) δ 5.90-5.88 (1H, m), 5.13-4.77 (2H, m), 4.31-4.27 (2H, m), 4.20-4.09 (2H, m), 4.00-3.86 (1H, m), 3.73-3.63 (3H, m), 3.48-3.31 (1H, m), 2.88-2.72 (1H, m), 2.62-2.49 (2H, m), 2.43-2.39 (1H, m), 2.24- 2.17 (2H, m), 1.42 (9H, s).

Mass (m / e) 461 (M + 1-BOC)

Example  89: 1-{(2S) -2-amino-4-oxo-4- [3- (pentafluoroethyl) -5,6-dihydro [1,2,4] triazolo [4,3-a ] Synthesis of pyrazin-7 (8H) -yl] butyl} -5,5-difluoropiperidin-2-one

In the same manner as in Example 22, t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3-oxo obtained from Preparation Example 149 -3- [3- (pentafluoroethyl) -5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazin-7 (8H) -yl] propyl} carbamate 63 24.7 mg (yield 44%) of the title compound were obtained from mg (0.112 mmol).

¹ H NMR (CD ₃ OD) δ 5.12-5.00 (2H, m), 4.42-4.39 (1H, m), 4.30 (1H, brs), 4.21-4.02 (2H, m), 3.89-3.75 (4H, m ), 3.62-3.54 (1H, m), 3.02-2.82 (2H, m), 2.65-2.56 (2H, m), 2.43-2.35 (2H, m)

Mass (m / e) 461 (M + 1)

Production Example  150: t-butyl {(1S) -1-{[(2S) -2-methyl-5-oxomorpholin-4-yl] methyl} -3-oxo-3- [3- ( Pentafluoroethyl ) -5,6- Dihydro [1,2,4] triazolo [4,3-a] pyrazin-7 (8H) -yl] propyl} Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(2S) -2-methyl-5-oxomorpholine-4- obtained from Preparation Example 55 3- (pentafluoroethyl) -5,6-dihydro [1,2,4] triazolo [obtained by reference to 56 mg (0.178 mmol) of il] -butanoic acid and JMC 2005, 48, p141-151. 43 mg (0.178 mmol) of 4,3-a] pyrazine was reacted to give 68 mg of the title compound (yield: 71%).

¹ H NMR (CDCl ₃ ) δ 5.90-5.88 (1H, m), 5.13-4.77 (2H, m), 4.29-4.09 (5H, m), 4.05-3.95 (2H, m), 3.86-3.69 (2H, m), 3.40-3.23 (3H, m), 2.91-2.72 (1H, m), 2.60-2.50 (1H, m), 1.42 (9H, brs), 1.27-1.25 (3H, m)

Mass (m / e) 441 (M + 1-BOC)

Example  90: (6S) -4-{(2S) -2-amino-4-oxo-4- [3- (pentafluoroethyl) -5,6-dihydro [1,2,4] Triazolo [4,3-a] pyrazin-7 (8H) -yl] butyl} -6- Methylmorpholine -3-one

T-butyl {(1S) -1-{[(2S) -2-methyl-5-oxomorpholin-4-yl] methyl} -3-oxo- obtained in the same manner as in Example 22 3- [3- (pentafluoroethyl) -5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazin-7 (8H) -yl] propyl} carbamate 68 mg (0.126 mmol) of 20.4 mg (yield: 30%) of the title compound was obtained.

¹ H NMR (CD ₃ OD) δ 5.11-5.00 (2H, m), 4.38 (1H, brs), 4.30 (1H, brs), 4.21-4.13 (3H, m), 4.10-4.05 (2H, m), 4.00-3.95 (1H, m), 3.80-3.75 (1H, m), 3.64-3.62 (2H, m), 3.36-3.33 (1H, m), 2.95-2.86 (1H, m), 2.82-2.76 (1H , m), 1.26 (3H, d, J = 6.0 Hz)

Mass (m / e) 441 (M + 1)

Production Example  151: t-butyl {(1S) -3- [2.4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] -1 -[(2- methyl -5- Oxothiomorpholine -4- days) methyl ] -3- Oxopro Phil} Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (2-methyl-5-oxothiomorpholin-4-yl)-obtained from Preparation Example 125 25 mg (0.075 mmol) of butanoic acid and 23 mg of 2,4-bis (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine hydrochloride (Preparation 127 , 0.075 mmol) to give 24.5 mg of the title compound (yield: 56%).

¹ H NMR (CDCl ₃ ) δ 5.91-5.81 (1H, m), 5.08-4.78 (2H, m), 4.13-3.98 (1H, m), 3.85-3.77 (2H, m), 3.70-3.66 (2H, m), 3.50-3.38 (2H, m), 3.27-3.22 (3H, m), 3.15-3.07 (2H, m), 2.88-2.81 (1H, m), 2.55-2.47 (1H, m), 1.42- 1.40 (9 H, m), 1.31-1.23 (3 H, m).

Mass (m / e) 486 (M + 1-BOC)

Example  91: 4-{(2S) -2-amino-4- [2.4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] Pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -6-methylthiomorpholin-3-one

T-butyl {(1S) -3- [2.4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] pyridine obtained in the same manner as in Example 22; Midin-7 (6H) -yl] -1-[(2-methyl-5-oxothiomorpholin-4-yl) methyl] -3-oxopropyl} carbamate from 24.5 mg (0.042 mmol) of the title compound 14.6 mg (yield 67%) were obtained.

¹ H NMR (CD ₃ OD) δ 5.00-4.85 (2H, m), 3.96-3.86 (3H, m), 3.71-3.59 (2H, m), 3.50-3.30 (5H, m), 3.22-3.19 (1H , m), 3.09 (1H, brs), 2.66-2.62 (1H, m), 2.60-2.50 (1H, m), 1.28-1.27 (3H, m)

Mass (m / e) 486 (M + 1)

Production Example  152: t-butyl {(1S) -3- [2-t-butyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 (6H) -Day] 1-1-[(5,5- Difluoro -2- Oxopiperidine -1 day) methyl ] -3-oxopropyl} Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidine-1 obtained from Preparation Example 57 -Yl] -butanoic acid 16.9 mg (0.050 mmol) with 2-t-butyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine 13.0 mg of hydrochloride (Preparation 131, 0.050 mmol) were obtained to give 19 mg of the title compound (yield: 66%).

¹ H NMR (CDCl ₃ ) δ 5.76 (1H, brs), 4.82 (1H, brs), 4.72-4.63 (1H, m), 4.20 (1H, brs), 3.87-3.85 (1H, m), 3.78-3.68 (3H, m), 3.62-3.53 (2H, m), 3.03-2.97 (1H, m), 2.84-2.80 (1H, m), 2.58-2.53 (4H, m), 2.29-2.20 (2H, m) , 1.41-1.38 (18H, m)

Mass (m / e) 475 (M + 1-BOC)

Example  92: 1-{(2S) -2-amino-4- [2-t-butyl-4- (trifluoromethyl) -5,8-dihydropyri Degree [3,4-d] pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -5,5-difluoropiperidin-2-one

In the same manner as in Example 22, t-butyl {(1S) -3- [2-t-butyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,] obtained from Production Example 152 4-d] pyrimidin-7 (6H) -yl] 1-1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3-oxopropyl} carbamate 11.0 mg (yield 92%) of the title compound were obtained from 19 mg (0.023 mmol).

¹ H NMR (CD ₃ OD) δ 4.86-4.79 (2H, m), 3.90-3.74 (4H, m), 3.50-3.43 (1H, m), 3.29 (2H, brs), 3.06 (1H, brs), 2.96 (1H, brs), 2.67-2.51 (4H, m), 2.35-2.30 (2H, m), 1.38-1.37 (9H, m)

Mass (m / e) 478 (M + 1)

Production Example  153: t-butyl [(1S) -3- [2-t-butyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] Pyrimidin-7 (6H) -yl] -1-{[(2S) -2- methyl -5- Oxomorpholine -4-day] methyl } -3- Oxopropyl ] Synthesis of Carbamate

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(2S) -2-methyl-5-oxomorpholine-4- obtained from Preparation Example 55 16 mg (0.050 mmol) of 1] -butanoic acid and 2-t-butyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- d ] pyrimidine hydrochloride 13 mg (Preparation 131, 0.050 mmol) were reacted to give 18 mg of the title compound (yield: 65%).

¹ H NMR (CDCl ₃ ) δ 5.75-5.74 (1H, m), 4.90-4.79 (1H, m), 4.65-4.60 (1H, m), 4.24-4.10 (3H, m), 3.92-3.87 (2H, m), 3.77-3.74 (1H, m), 3.67-3.62 (1H, m), 3.55-3.49 (1H, m), 3.40-3.31 (2H, m), 3.04-2.98 (2H, m), 2.86- 2.83 (1H, m), 2.58-2.55 (1H, m), 1.43-1.42 (9H, m), 1.39-1.38 (9H, s), 1.28-1.24 (3H, m).

Mass (m / e) 458 (M + 1-BOC)

Example  93: (6S) -4-{(2S) -2-amino-4- [2-t-butyl-4- (trifluoromethyl) -5,8-dihydrate Ropyrido [3,4- d ] Pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -6-methylmorpholin-3-one

In the same manner as in Example 22, t-butyl [(1S) -3- [2-t-butyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,] obtained from Production Example 153 4- d ] pyrimidin-7 (6H) -yl] -1-{[(2S) -2-methyl-5-oxomorpholin-4-yl] methyl} -3-oxopropyl] carbamate 18 mg (0.022 mmol) of 10.2 mg (yield 94%) of the title compound.

¹ H NMR (CD ₃ OD) δ 4.86-4.75 (2H, m), 4.16-4.05 (2H, m), 3.94-3.89 (1H, m), 3.86-3.81 (1H, m), 3.55-3.50 (2H , m), 3.40-3.28 (4H, m), 3.07-3.05 (1H, m), 2.96 (1H, brs), 2.70-2.65 (1H, m), 2.57-2.52 (1H, m), 1.38-1.37 (9H, m), 1.22 (3H, doublet, J = 6.2 Hz).

Mass (m / e) 458 (M + 1)

Production Example  154: t-butyl {(1S) -1-[(2-methyl-5-oxothiomorpholin-4-yl) methyl] -3-oxo-3- [3- ( Trifluoromethyl ) -5,6- Dihydro [1,2,4] triazolo Synthesis of [4,3-a] pyrazin-7 (8H) -yl] propyl} carbamate

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (2-methyl-5-oxothiomorpholin-4-yl)-obtained from Preparation Example 125 3- (trifluoromethyl) -5,6-dihydro-8H-1,2,4-triazolo [4,3- synthesized with reference to 25 mg (0.075 mmol) butanoic acid and WO 03/004498 a] Reaction with 14.4 mg (0.075 mmol) of pyrazine gave 21 mg of the title compound (yield: 55%).

¹ H NMR (CDCl ₃ ) δ 5.95-5.86 (1H, m), 5.12-4.80 (3H, m), 4.30-4.06 (3H, m), 3.99-3.90 (2H, m), 3.67-3.53 (2H, m), 3.42-3.35 (1H, m), 3.30-3.06 (3H, m), 2.90-2.74 (1H, m), 2.52-2.47 (1H, m), 1.40 (9H, s), 1.29-1.28 ( 3H, m).

Mass (m / e) 407 (M + 1-BOC)

Example  94: 4-{(2S) -2-amino-4-oxo-4- [3- ( Trifluoromethyl Synthesis of) -5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazin-7 (8H) -yl] butyl} -6-methylthiomorpholin-3-one

In the same manner as in Example 22, t-butyl {(1S) -1-[(2-methyl-5-oxothiomorpholin-4-yl) methyl] -3-oxo-3- [obtained from Production Example 154. 21 mg (0.042 mmol) of 3- (trifluoromethyl) -5,6-dihydro [1,2,4] triazolo [4,3-a] pyrazin-7 (8H) -yl] propyl} carbamate ) Gave 5.8 mg (yield: 34%) of the title compound.

¹ H NMR (CD ₃ OD) δ 5.08-4.98 (2H, m), 4.34 (1H, brs), 4.26 (1H, brs), 4.20-4.06 (2H, m), 3.74-3.69 (2H, m), 3.62 (1H, brs), 3.50-3.37 (4H, m), 3.32-3.23 (1H, m), 2.08-2.75 (1H, m), 2.68-2.62 (1H, m), .33-1.31 (3H, m).

Mass (m / e) 407 (M + 1)

Production Example  155: t-butyl {(1S) -3- [2-ethyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl ] -1-{[(5R) -5- methyl -2- Oxopiperidine -1 day] methyl } -3- Oxopropyl } Synthesis of Carbamate

In the same manner as in Production Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(5R) -5-methyl-2-oxopiperidine-1 obtained from Production Example 51 -Yl] -butanoic acid 66.3 mg (0.211 mmol) with 2-ethyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine hydrochloride 41 mg (Preparation 128, 0.192 mmol) were reacted to give 63 mg of the title compound (yield: 62%).

¹ H NMR (CDCl ₃ ) δ 5.87 (1H, brs), 4.89-4.79 (1H, m), 4.76-4.65 (1H, m), 4.17 (1H, brs), 3.91-3.86 (1H, m), 3.78 -3.75 (1H, m), 3.67-3.50 (2H, m), 3.89-3.35 (1H, m), 3.10-2.97 (6H, m), 2.88-2.81 (1H, m), 2.55-2.28 (3H, m), 1.95-1.88 (1H, m), 1.84-1.80 (1H, m), 1.42-1.40 (9H, m), 1.38-1.34 (3H, m), 1.01-0.99 (3H, m).

Mass (m / e) 438 (M + 1-BOC)

Example  95: (5R) -1-{(2S) -2-Amino-4- [2-ethyl-4- (trifluoromethyl) -5,8-dihydro Pyrido [3,4- d ] Pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one

T-butyl {(1S) -3- [2-ethyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4- obtained from Preparation Example 155 in the same manner as in Example 22 d ] pyrimidin-7 (6H) -yl] -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxopropyl} carbamate 63 mg ( 0.119 mmol) to give 38.3 mg (yield 69%) of the title compound.

¹ H NMR (CD ₃ OD) δ 4.92-4.80 (2H, m), 3.94-3.91 (1H, m), 3.88-3.85 (1H, m), 3.78-3.76 (1H, m), 3.69-3.62 (1H , m), 3.58-3.53 (1H, m), 3.42-3.34 (2H, m), 3.15-3.09 (2H, m), 3.03-2.97 (2H, m), 2.92-2.85 (1H, m), 2.79 -2.73 (1H, m), 2.48-2.34 (2H, m), 2.06-2.02 (1H, m), 1.89-1.84 (1H, m), 1.60-1.49 (1H, m), 1.41-1.35 (3H, m), 1.05 (3H, d, J = 6.4 Hz).

Mass (m / e) 428 (M + 1)

Production Example  156: t-butyl  {(1S) -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxo-3- [2- ( Pentafluoroethyl )-4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4- d ] Pyrimidine Synthesis of -7 (6H) -yl] propyl} carbamate

In the same manner as in Production Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(5R) -5-methyl-2-oxopiperidine-1 obtained from Production Example 51 -Yl] -butanoic acid 43 mg (0.137 mmol) with 2- (pentafluoroethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- d ] 40 mg of pyrimidine hydrochloride (Preparation 129, 0.125 mmol) gave 65 mg of the title compound (yield: 84%).

¹ H NMR (CDCl ₃ ) δ 5.98-5.91 (1H, m), 5.30-4.79 (2H, m), 4.14-4.02 (2H, m), 3.89-3.81 (2H, m), 3.69-3.47 (2H, m), 3.40-3.34 (1H, m), 3.24-3.01 (3H, m), 2.89-2.79 (1H, m), 2.57-2.43 (1H, m), 2.40-2.19 (2H, m), 1.94 ( 1H, brs), 1.84 (1H, brs), 1.42-1.40 (9H, m), 1.00 (3H, d, J = 6.4 Hz).

Mass (m / e) 518 (M + 1-BOC)

Example  96: (5R) -1-{(2S) -2-amino-4-oxo-4- [2- (pentafluoroethyl) -4- (trifluoro Rhomethyl ) -5,8- Dihydropyrido [3,4- d ] Pyrimidine -7 (6H) -yl] butyl} -5- Methylpiperidine Synthesis of 2-one

T-butyl {(1S) -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxo, obtained in the same manner as in Example 22, from Production Example 156 -3- [2- (pentafluoroethyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrimidin-7 (6H) -yl] propyl} carbox 653.9 mg (0.104 mmol) of barmate gave 43.9 mg (yield: 82%) of the title compound.

¹ H NMR (CD ₃ OD) δ 4.99-4.95 (1H, m), 3.99-3.87 (3H, m), 3.69-3.68 (1H, m), 3.56-3.53 (2H, m), 3.41-3.38 (1H , m), 3.25 (1H, brs), 3.15-3.06 (2H, m), 2.84-2.77 (1H, m), 2.72-2.62 (1H, m), 2.45-2.34 (2H, m), 2.03 (1H , brs), 1.85 (1H, brs), 1.58-1.48 (1H, m), 1.05 (3H, d, J = 6.4 Hz).

Mass (m / e) 518 (M + 1)

Production Example  157: t-butyl  {(1S) -1-{[(2S) -2-methyl-5-oxomorpholin-4-yl] methyl} -3-oxo-3- [2- ( Pentafluoroethyl )-4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] propyl} Carbamate  synthesis

In the same manner as in Preparation Example 145, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(2S) -2-methyl-5-oxomorpholine-4- obtained from Preparation Example 55 4] mg (0.137 mmol) of 1] -butanoic acid and 2- (pentafluoroethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d] 40 mg of pyrimidine hydrochloride (Preparation 129, 0.125 mmol) were obtained to give 58 mg of the title compound (yield: 75%).

¹ H NMR (CDCl ₃ ) δ 5.87-5.84 (1H, m), 5.09-4.79 (2H, m), 4.23-3.98 (3H, m), 3.89-3.80 (2H, m), 3.72-3.65 (1H, m), 3.46-3.33 (4H, m), 3.22-3.13 (2H, m), 2.90-2.81 (1H, m), 2.61-2.50 (1H, m), 1.43-1.41 (9H, m), 1.26 ( 3H, d, J = 6.0 Hz).

Mass (m / e) 520 (M + 1-BOC)

Example  97: (6S) -4-{(2S) -2-amino-4-oxo-4- [2- (pentafluoroethyl) -4- (trifluoro Rhomethyl ) -5,8-dihydropyrido [3,4- d ] Synthesis of Pyrimidin-7 (6H) -yl] butyl} -6-methylmorpholin-3-one

T-butyl {(1S) -1-{[(2S) -2-methyl-5-oxomorpholin-4-yl] methyl} -3-oxo- obtained in the same manner as in Example 22 3- [2- (pentafluoroethyl) -4- (trifluoro) -5,8-dihydropyrido [3,4- d ] pyrimidin-7 (6H) -yl] propyl} carbamate 58 mg (0.094 mmol) of 43.9 mg (yield: 90%) of the title compound were obtained.

¹ H NMR (CD ₃ OD) δ 4.99-4.95 (1H, m), 4.21-4.10 (2H, m), 4.05-3.90 (3H, m), 3.64-3.54 (2H, m), 3.50-3.39 (2H , m), 3.62-3.35 (2H, m), 3.24 (1H, brs), 3.14 (1H, brs), 2.79-2.73 (1H, m), 2.67-2.58 (1H, m), 1.26 (3H, d , J = 6.0 Hz).

Mass (m / e) 520 (M + 1)

Production Example  158: t-butyl  {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3-oxo-3- [2- ( Pentafluoroethyl )-4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimi Din-7 (6H) -yl] propyl} Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidine-1 obtained from Preparation Example 57 -Yl] -butanoic acid 46 mg (0.137 mmol) with 2- (pentafluoroethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d ] 40 mg of pyrimidine hydrochloride (Preparation 129, 0.125 mmol) gave 16.4 mg of the title compound (yield: 47%).

¹ H NMR (CDCl ₃ ) δ 5.85-5.78 (1H, m), 5.07-4.79 (2H, m), 4.17 (1H, brs), 4.04-3.61 (5H, m), 3.53-3.49 (1H, m) , 3.19-3.13 (2H, m), 2.87-2.79 (1H, m), 2.62-2.48 (3H, m), 2.32-2.24 (2H, m), 1.42-1.41 (9H, m)

Mass (m / e) 540 (M + 1-BOC)

Example  98: 1-{(2S) -2-amino-4-oxo-4- [2- (pentafluoroethyl) -4- (trifluoromethyl) -5,8- Dihydropyrido [3,4- d ] Pyrimidine -7 (6H) -yl] butyl} -5,5- Difluoropiperidine Synthesis of 2-one

In the same manner as in Example 22, t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3-oxo obtained from Production Example 158 -3- [2- (pentafluoroethyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrimidin-7 (6H) -yl] propyl} carbox 642.8 mg (0.095 mmol) of bamate gave 42.8 mg (yield: 83%) of the title compound.

¹ H NMR (CD ₃ OD) δ 4.98-4.95 (1H, m), 4.03-3.89 (2H, m), 3.85-3.77 (2H, m), 3.64-3.54 (2H, m), 3.52-3.46 (1H m), 3.26-3.24 (1H, m), 3.14 (1H, brs), 2.80-2.72 (1H, m), 2.68-2.56 (4H, m), 2.04-2.03 (2H, m).

Mass (m / e) 540 (M + 1)

Production Example  159: 2-propyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d] pi Limidine  Synthesis of Hydrochloride

(One) Butaneimidamide  synthesis

In the same manner as in Production Example 58 (1), 2.0 g (1.85 mmol) of butyronitrile was obtained 1.95 g (yield: 79%) of the title compound.

NMR: ¹ H-NMR (CD ₃ OD) δ 2.45 (2H, t, J = 6.5 Hz), 1.75 (2H, m), 1.05 (3H, t, J = 7.2 Hz)

(2) t-butyl 2-propyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 (6H) -car Leboxile Synthesis of sites

In the same manner as in Production Example 58 (2), 500 mg (1.69 mmol) of t-butyl 3-oxo-4- (trifluoroacetyl) piperidine-1-carboxylate and butane obtained from step (1) 146 mg (1.69 mmol) of imidamide were used to yield 144 mg (yield: 25%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 4.73 (2H, s), 3.76 (2H, t, J = 8.0 Hz), 3.00 (4H, m), 1.89 (2H, m), 1.54 (9H, s), 1.06 ( 3H, t, J = 8 Hz)

Mass (m / e) 346 (M + 1)

(3) 2-propyl-4- ( Trifluoromethyl ) -5,6,7,8- Tetrahydropyrido [3,4-d] pyrimidine  Synthesis of Hydrochloride

T-butyl 2-propyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrile obtained in the same manner as in Production Example 58 (3), from step (2). 144 mg (0.42 mmol) of midine-7 (6H) -carboxylate gave 72 mg (yield: 61%) of the title compound.

¹ H NMR (CD ₃ OD) δ 4.46 (2H, s), 3.59 (2H, t, J = 6.0 Hz), 3.25 (2H, m), 2.94 (2H, t, J = 7.2 Hz), 1.84 (2H , m), 0.97 (3H, t, J = 7.2 Hz)

Mass (m / e) 246 (M + 1)

Production Example  160: t-butyl  {(1S) -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxo-3- [2-propyl-4- ( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] propyl} Carbamate  synthesis

In the same manner as in Production Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(5R) -5-methyl-2-oxopiperidine-1 obtained from Production Example 51 -Yl] -butanoic acid 44.0 mg (0.141 mmole) and 2-propyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d from Preparation Example 159 ] Isolation and purification using 36.0 mg (0.128 mmole) of pyrimidine hydrochloride gave 70 mg (yield: 91%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 5.88 (1H, brs), 4.89-4.65 (2H, m), 4.18 (1H, brs), 3.89-3.86 (1H, m), 3.78-3.76 (1H, m), 3.62 -51 (2H, m), 3.38-3.35 (1H, m), 3.11-2.80 (7H, m), 2.56-2.28 (3H, m), 1.94-1.82 (4H, m), 1.42-1.40 (9H, m), 1.01-0.98 (6H, m).

Mass (m / e) 542 (M + 1)

Example  99: (5R) -1-{(2S) -2-amino-4-oxo-4- [2-propyl-4- ( Trifluoromethyl Synthesis of) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] butyl} -5-methylpiperidin-2-one

T-butyl {(1S) -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxo- obtained from Production Example 160 in the same manner as in Example 22 70 mg (0.129) of 3- [2-propyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] propyl} carbamate mmol) gave 41.9 mg (yield 68%) of the title compound.

¹ H NMR (CD ₃ OD) δ 4.86-4.79 (2H, m), 3.95-3.82 (2H, m), 3.67-3.64 (1H, m), 3.59-3.47 (2H, m), 3.41-3.37 (1H , m), 3.34-3.32 (1H, m), 3.11-3.10 (2H, m), 3.01-2.93 (2H, m), 2.79-2.73 (1H, m), 2.67-2.57 (1H, m), 2.47 -2.31 (2H, m), 2.04-2.00 (1H, m), 1.92-1.82 (3H, m), 1.58-1.48 (1H, m), 1.06 (3H, d, J = 6.4 Hz), 1.03-0.99 (3H, m).

Mass (m / e) 442 (M + 1)

Production Example  161: t-butyl  {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3-oxo-3- [2-propyl-4- ( Trifluoromethyl ) -5,8- Dihydropyrido [3,4- d ] Pyrimidine -7 (6H) -yl] propyl} Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidine-1 obtained from Preparation Example 57 -Yl] -butanoic acid 47.0 mg (0.141 mmol) and 2-propyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- d from Preparation Example 159 ] Isolation and purification using 36.0 mg (0.128 mmol) of pyrimidine hydrochloride gave 61 mg (yield: 77%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 5.78 (1H, brs), 4.83-4.68 (2H, m), 4.20 (1H, brs), 3.88-3.68 (4H, m), 3.60-3.56 (2H, m), 3.04 -2.78 (5H, m), 2.61-2.55 (3H, m), 2.31-2.23 (2H, m), 1.87-1.82 (2H, m), 1.42-1.41 (9H, m), 1.02-0.98 (3H, m).

Mass (m / e) 564 (M + 1)

Example  100: 1-{(2S) -2-amino-4-oxo-4- [2-propyl-4- (trifluoromethyl) -5,8-dich Dropyrido [3,4- d ] Pyrimidine Synthesis of -7 (6H) -yl] butyl} -5,5-difluoropiperidin-2-one

In the same manner as in Example 22, t-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3-oxo obtained from Preparation Example 161 47 mg of 3- [2-propyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d ] pyrimidin-7 (6H) -yl] propyl} carbamate 0.081 mmol) to give 34.4 mg (yield: 64%) of the title compound.

¹ H NMR (CD ₃ OD) δ 4.90-4.79 (2H, m), 3.86-3.78 (4H, m), 3.57-3.46 (3H, m), 3.12-3.10 (1H, m), 3.00-2.93 (3H , m), 2.76-2.51 (4H, m), 2.41-2.31 (2H, m), 1.92-1.82 (2H, m), 1.03-0.95 (3H, m).

Mass (m / e) 464 (M + 1)

Preparation Example 162 Synthesis of 2- ( fluoromethyl ) -4- ( trifluoromethyl ) -5,6,7,8- tetrahydropyrido [3,4-d] pyrimidine hydrochloride

(One) 2- Of fluoroethane imidamide  synthesis

In the same manner as in Production Example 58 (1), 1.77 g (yield 93%) of the title compound was obtained using 1.5 g (0.025 mmol) of fluoroacetonitrile.

NMR: ¹ H-NMR (CD ₃ OD) δ 5.32 (2H, d, J = 45.2 Hz)

(2) t-butyl 2- ( Fluoromethyl )-4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] Pyrimidine-7 (6H)- Carboxylate  synthesis

In the same manner as in Production Example 58 (2), 1.0 g (3.39 mmol) of t-butyl 3-oxo-4- (trifluoroacetyl) piperidine-1-carboxylate and 2 obtained from step (1) were used. 220 mg (yield 19%) of the title compound were obtained using 335 mg (4.40 mmol) of -fluoroethaneimidamid.

¹ H NMR (CDCl ₃ ) δ 5.55 (2H, d, J = 46.8 Hz), 4.78 (2H, s), 3.75 (2H, t, J = 6.0 Hz), 3.00 (2H, brs), 1.50 (9H, s)

Mass (m / e) 336 (M + 1)

(3) 2-( Fluoromethyl )-4-( Trifluoromethyl ) -5,6,7,8- Tetrahydropyrido [3,4-d] Synthesis of Pyrimidine Hydrochloride

In the same manner as in Production Example 58 (3), t-butyl 2- (fluoromethyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3, 170 mg (yield: 96%) of the title compound were obtained using 220 mg (0.66 mmol) of 4-d] pyrimidine-7 (6H) -carboxylate.

¹ H NMR (CD ₃ OD) δ 5.57 (2H, d, J = 29.6 Hz), 4.76 (2H, s), 4.47 (2H, s), 3.26-3.20 (2H, m),

Mass (m / e) 236 (M + 1)

Production Example  163: t-butyl [(1S) -3- [2- (fluoromethyl) -4- (trifluoromethyl) -5,8-dihydrate Ropyrido [3,4-d] pyrimidine -7 (6H) -yl] -1-{[(5R) -5- methyl -2- Oxopiperidine -1 day] methyl } -3-jade Sopro Phil] Carbamate  synthesis

In the same manner as in Production Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4-[(5R) -5-methyl-2-oxopiperidine-1 obtained from Production Example 51 -Yl] -butanoic acid 125 (0.398 mmole) and 2- (fluoromethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3] from Preparation Example 162 , 4-d] pyrimidine hydrochloride was separated and purified using 85 mg (0.361 mmole) to obtain 115 mg (yield: 60%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 5.90-5.88 (1H, m), 5.54 (2H, dd, J = 46.5, 2.75 Hz), 4.97-4.72 (2H, m), 4.14 (1H, brs), 3.90 (1H , brs), 3.80-3.70 (1H, m), 3.55-3.52 (2H, m), 3.37-3.33 (1H, m), 3.10-2.98 (3H, m), 2.43-2.28 (4H, m), 1.45 -1.38 (9H, m), 0.99 (3H, d, J = 6.8 Hz).

Mass (m / e) 532 (M + 1)

Example  101: (5R) -1-{(2S) -2-Amino-4- [2- (fluoromethyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4- d] Synthesis of pyrimidin-7 (6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one

T-butyl {(1S) -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxo, obtained in the same manner as in Example 22, from Production Example 163 70 mg of -3- [2-propyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] propyl} carbamate 0.129 mmole) gave 41.9 mg (yield 68%) of the title compound.

¹ H NMR (CD ₃ OD) δ 4.86-4.79 (2H, m), 3.95-3.82 (2H, m), 3.67-3.64 (1H, m), 3.59-3.47 (2H, m), 3.41-3.37 (1H , m), 3.34-3.32 (1H, m), 3.11-3.10 (2H, m), 3.01-2.93 (2H, m), 2.79-2.73 (1H, m), 2.67-2.57 (1H, m), 2.47 -2.31 (2H, m), 2.04-2.00 (1H, m), 1.92-1.82 (3H, m), 1.58-1.48 (1H, m), 1.06 (3H, d, J = 6.4 Hz), 1.03-0.99 (3H, m).

Mass (m / e) 432 (M + 1)

Production Example  164: t-butyl  {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3- [2- ( Fluoromethyl )-4-( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -3- Oxopropyl } Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidine-1 obtained from Preparation Example 57 2- (fluoromethyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3] -yl] -butanoic acid from 134 mg (0.398 mmole) and preparation 162. , 4-d] pyrimidine hydrochloride was separated and purified using 85.0 mg (0.361 mmole) to obtain 85 mg (yield: 43%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 5.80-5.78 (1H, brs), 5.47 (2H, d, J = 24.4 Hz), 4.96-4.72 (2H, m), 4.18 (1H, brs), 3.91-3.89 (1H , m), 3.80-3.49 (5H, m), 3.11-3.00 (2H, m), 2.84-2.77 (1H, m), 2.59-2.48 (3H, m), 2.29-2.21 (2H, m), 1.42 -1.40 (9H, m)

Mass (m / e) 554 (M + 1)

Example  102: 1-{(2S) -2-amino-4- [2- (fluoromethyl) -4- (trifluoromethyl) -5,8-di Hydropyrido [3,4-d] pyrimidine -7 (6H) -yl] -4- Oxobutyl } -5,5- Difluoropiperidine Synthesis of 2-one

T-butyl {(1S) -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3- [obtained in Preparation 164 in the same manner as in Example 22 2- (fluoromethyl) -4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] -3-oxopropyl} carba 47 mg (0.081 mmole) of mate gave 34.4 mg (64% yield) of the title compound.

¹ H NMR (CD ₃ OD) δ 4.90-4.79 (2H, m), 3.86-3.78 (4H, m), 3.57-3.46 (3H, m), 3.12-3.10 (1H, m), 3.00-2.93 (3H , m), 2.76-2.51 (4H, m), 2.41-2.31 (2H, m), 1.92-1.82 (2H, m), 1.03-0.95 (3H, m).

Mass (m / e) 464 (M + 1)

Production Example  165: t-butyl (3S) -3-[(t-butoxycarbonyl) amino] -4- (4-methyl-2-oxo-2,5-dihydro-1 H-pyrrol-1-yl) Butanoate  synthesis

In the same manner as in Production Example 42, 4-amino-3-methyl-2- obtained from 3S-t-butoxycarbonylamino-4-oxo-butyric acid t-butylester obtained in Production Example 41 and Production Example 6 590 mg (3.56 mmol) of butenoic acid methyl ester hydrochloride were used to obtain 410 mg (yield 34%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 6.03 (1H, s), 5.34-5.31 (1H, m), 4.15-3.84 (3H, m), 3.71-3.62 (1H, m), 3.41-3.36 (1H, m) , 2.54-2.38 (2H, m), 2.07-2.04 (3H, m), 1.45 (9H, s), 1.39 (9H, s)

Mass (m / e) 355 (M + 1)

Production Example  166: (3S) -3-[(t-butoxy Carbonyl ) Amino] -4- (4- methyl -2-oxo-2,5- Dehydro -1H-pyrrole-1-yl) Butanoic  synthesis

T-butyl (3S) -3-[(t-butoxycarbonyl) amino] -4- (4-methyl-2-oxo-2,5-di obtained in the same manner as in Production Example 43 410 mg (1.16 mmol) of hydro-1H-pyrrole-1-yl) butanoate gave 310 mg (yield 90%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 9.03 (1H, brs), 6.12 (1H, s), 5.73 (1H, d, J = 8.8 Hz), 4.16-4.11 (2H, m), 3.94-3.90 (1H, m ), 3.78-3.72 (1H, m), 3.50-3.45 (1H, m), 2.66-2.54 (2H, m), 2.07 (3H, s), 1.39 (9H, s)

Mass (m / e) 299 (M + 1)

Production Example  167: t-butyl (3S) -3-[(t-butoxycarbonyl) amino] -4- (4-methyl-2-oxopyrrolidin-1-yl) Butanoate  synthesis

In the same manner as in Preparation Example 42, 1.03 g (yield 64%) of the title compound was obtained using 790 mg (4.71 mmol) of 4-amino-3-methyl-butyric acid methyl ester hydrochloride obtained from Preparation Example 2.

Mass (m / e) 357 (M + 1)

Production Example  168: Synthesis of (3S) -3-[(t-butoxycarbonyl) amino] -4- (4-methyl-2-oxopyrrolidin-1-yl) butanoic acid

T-butyl (3S) -3-[(t-butoxycarbonyl) amino] -4- (4-methyl-2-oxopyrrolidine-1- obtained in the same manner as in Production Example 43 Il) butanoate 1.03 g (2.89 mmol) gave 670 mg (yield 77%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 6.96 (1H, brs), 5.97-5.55 (1H, m), 4.16 (1H, brs), 3.78-3.40 (2H, m), 3.27-2.99 (1H, m), 2.66 -2.47 (4H, m), 2.14-2.05 (1H, m), 1.44-1.42 (9H, s), 1.12 (3H, d, J = 8.0 Hz)

Mass (m / e) 301 (M + 1)

Production Example  169: t-butyl (3S) -3-[(t-butoxycarbonyl) amino] -4- [2-oxo-5- (trifluoromethyl) piperidin-1-yl] Butanoate  synthesis

In the same manner as in Preparation 42, 49 mg of the title compound (yield 22) using 132 mg (0.558 mmol) of 4-aminomethyl-5,5,5-trifluoro-pentanoic acid methyl ester hydrochloride obtained from Preparation Example 11 %) Was obtained.

¹ H NMR (CDCl ₃ ) δ 5.56-5.25 (1H, m), 4.40 (1H, br s), 3.85-3.46 (1H, m), 3.42-3.36 (1H, m), 3.32-2.27 (1H, m ), 2.62-2.36 (4H, m), 2.13-2.05 (2H, m), 1.92-1.79 (2H, m), 1.46 (9H, s), 1.42-1.41 (9H, m)

Mass (m / e) 425 (M + 1)

Production Example  170: (3S) -3-[(t-butoxycarbonyl) amino] -4- [2-oxo-5- (trifluoromethyl) piperidin-1-yl]- Butanoic  synthesis

T-butyl (3S) -3-[(t-butoxycarbonyl) amino] -4- [2-oxo-5- (trifluoromethyl) pi obtained in the same manner as in Preparation Example 43 49 mg (0.115 mmol) of ferridin-1-yl] butanoate gave 14 mg (yield 13%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 4.25 (1H, br s), 3.68-3.48 (4H, m), 2.83 (2H, brs), 2.56-2.36 (2H, m), 2.16-2.10 (2H, m), 1.96-1.84 (2H, m), 1.47-1.44 (9H, s)

Mass (m / e) 369 (M + 1)

Production Example  171: t-butyl (3S) -3-[(t-butoxycarbonyl) amino] -4- [2-oxo-4- (trifluoromethyl) Pyrrolidine -1 day] Butanoate  synthesis

134 mg (yield 21%) of the title compound using 390 mg (1.65 mmol) of 3-aminomethyl-4,4,4-trifluoro-butyric acid ethyl ester hydrochloride obtained from Preparation Example 1 in the same manner as Preparation Example 42 )

¹ H NMR (CDCl ₃ ) δ 5.10-5.09 (1H, brs), 4.12 (1H, br s), 3.67-3.50 (3H, m), 3.28-3.25 (1H, m), 3.10-3.04 (1H, m ), 2.64-2.50 (2H, m), 2.44-2.40 (2H, m), 1.47 (9H, s), 1.40 (9H, s)

Mass (m / e) 411 (M + 1)

Production Example  172: (3S) -3-[(t-butoxycarbonyl) amino] -4- [2-oxo-4- (trifluoromethyl) pyrrolidin-1-yl]- Butanoic  synthesis

T-butyl (3S) -3-[(t-butoxycarbonyl) amino] -4- [2-oxo-4- (trifluoromethyl) pi obtained in the same manner as in Preparation Example 171 89 mg (yield 78%) of the title compound were obtained using 134 mg (0.326 mmol) of rollidin-1-yl] butanoate.

Mass (m / e) 355 (M + 1)

Production Example  173: t-butyl (3S) -3-[(t-butoxycarbonyl) amino] -4- (4-methyl-2-oxooxopiperidin-1-yl) Butanoate  synthesis

750 mg (yield 62%) of the title compound were obtained using 620 mg (3.43 mmol) of 5-amino-3-methyl-pentanoic acid methyl ester hydrochloride obtained from Preparation Example 8 in the same manner as in Preparation Example 42.

¹ H NMR (CDCl ₃ ) δ 5.35-5.30 (1H, m), 4.17 (1H, brs), 3.95-3.86 (1H, m), 3.78-3.64 (1H, m), 3.51-3.46 (1H, m) , 3.30-3.26 (1H, m), 3.16-3.02 (1H, m), 2.54-2.46 (2H, m), 2.41-2.34 (1H, m), 2.01-1.84 (3H, m), 1.45 (9H, s), 1.41 (9H, s), 1.01 (3H, d, J = 6.0 Hz)

Mass (m / e) 371 (M + 1)

Production Example  174: (3S) -3-[(t-butoxy Carbonyl ) Amino] -4- (4- methyl -2- Oxopiperidine Synthesis of -1-yl) -butanoic acid

T-butyl (3S) -3-[(t-butoxycarbonyl) amino] -4- (4-methyl-2-oxooxopiperidine-1 obtained in the same manner as in Production Example 43 750 mg (2.02 mmol) of -yl) butanoate gave 579 mg (yield 92%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 7.93 (1H, brs), 5.05-5.57 (1H, m), 4.20-4.19 (1H, m), 3.90-3.74 (1H, m), 3.57-3.51 (1H, m) , 3.41-3.23 (2H, m), 2.66-2.52 (3H, m), 2.07-1.86 (3H, m), 1.33 (9H, s), 1.01 (3H, d, J = 6.4 Hz)

Mass (m / e) 315 (M + 1)

Production Example  175: t-butyl  {(1S) -3- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] -1-[( 4- methyl -2-oxo-2,5- Dehydro -1H-pyrrole-1-yl) methyl -3-jade Sopro Phil} Carbamate  synthesis

In the same manner as in Production Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (4-methyl-2-oxo-2,5-dihydro-1H obtained from Production Example 166. 2,4-bis (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4 obtained from 25.0 mg (0.084 mmol) of -pyrrol-1-yl) butanoic acid and Preparation Example 127 -d] Pyrimidine hydrochloride was separated and purified using 25.8 mg (0.084 mmol) to obtain 45.0 mg (yield 98%) of the title compound.

¹ H NMR (CDCl ₃ )) δ 6.12-5.99 (1H, m), 5.79 (1H, d, J = 16.0 Hz), 5.09-4.84 (2H, m), 4.18-4.13 (1H, m), 4.07- 3.91 (3H, m), 3.74-3.66 (1H, m), 3.58-3.53 (1H, m), 3.30-3.13 (3H, m), 2.95-2.83 (1H, m), 2.60-2.55 (1H, m ), 2.09 (3H, d, J = 1.2 Hz), 1.45-1.43 (9H, m)

Mass (m / e) 552 (M + 1)

Example  103: 1-{(2S) -2-amino-4- [2,4- Vis ( Trifluoromethyl ) -5,8- Dihydropyrido [3,4-d] pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -4-methyl-1,5-dihydro-2H-pyrrol-2-one

T-butyl {(1S) -3- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4-d obtained from Preparation Example 175 in the same manner as in Example 22 ] Pyrimidin-7 (6H) -yl] -1-[(4-methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl) methyl] -3-oxopropyl} carbamate 45.0 mg (0.0816 mmol) of 25.7 mg (65% yield) of the title compound were obtained.

¹ H NMR (CD ₃ OD) δ 5.86-5.84 (1H, m), 4.99-4.97 (2H, m), 4.14-4.13 (2H, m), 4.10-3.91 (3H, m), 3.78-3.70 ( 2H, m), 3.25 (1H, brs), 3.14 (1H, brs), 3.10-3.00 (1H, m), 2.88-2.82 (1H, m), 2.14 (3H, s)

Mass (m / e) 452 (M + 1)

Production Example  201: t-butyl  {(1S) -3- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydropyri Degree [3,4-d] pyrimidine -7 (6H) -yl] -1-[(4- methyl -2-oxo-2,5- Dehydro -1H-pyrrole-1-yl) methyl ] -3-jade Sopro Phil} Carbamate  synthesis

In the same manner as in Production Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (4-methyl-2-oxo-2,5-dihydro-1H obtained from Production Example 166. 2- (3-furyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyri obtained from 25 mg (0.084 mmol) of pyrrole-1-yl) butanoic acid and Preparation Example 96 Separation and purification using 25.6 mg (0.084 mmol) of Fig. 3,4-d] pyrimidine hydrochloride gave 44.9 mg (yield 97%) of the title compound.

¹ H NMR (CDCl ₃ )) δ 8.27 (1H, s), 7.50-7.49 (1H, m), 7.06-7.05 (1H, m), 6.04- 5.90 (1H, m), 5.80-5.79 (1H, m ), 4.85 (1H, s), 4.83-4.70 (1H, m), 4.15-4.07 (1H, m), 4.02-3.95 (2H, m), 3.92-3.87 (1H, m), 3.84-3.81 (1H , m), 3.69-3.55 (2H, m), 3.08-3.06 (1H, m), 2.99 (1H, brs), 2.91-2.83 (1H, m), 2.57-2.52 (1H, m), 2.05-2.04 (3H, m), 1.41-1.40 (9H, m)

Mass (m / e) 550 (M + 1)

Example  104: 1-{(2S) -2-amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydro Pyrido [3,4-d] pyrimidine -7 (6H) -yl] -4- Oxobutyl }-4- methyl -1,5- Dehydro Synthesis of -2H-pyrrole-2-one

In the same manner as in Example 22, t-butyl {(1S) -3- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydropyrido [obtained from Preparation Example 176 [ 3,4-d] pyrimidin-7 (6H) -yl] -1-[(4-methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl) methyl] -3-oxo 32.7 mg (82% yield) of the title compound were obtained from 44.9 mg (0.0817 mmol) of propyl} carbamate.

¹ H NMR (CD ₃ OD)) δ 8.35 (1H, s), 7.69-7.64 (1H, m), 7.08 (1H, s), 6.10 (1H, brs), 4.90-4.88 (2H, m), 4.23 (1H, brs), 3.95-3.81 (5H, m), 3.77-3.65 (1H, m), 3.19-3.03 (3H, m), 2.94-2.87 (1H, m), 2.15 (3H, m)

 Mass (m / e) 450 (M + 1)

Production Example  177 t-butyl {(1S) -3- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] -1-[(4- methyl -2- Oxopyrrolidine -1 day) methyl ] -3- Oxopro Phil} Carbamate  synthesis

In the same manner as in Production Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (4-methyl-2-oxopyrrolidin-1-yl) buta obtained from Production Example 168 35.0 mg (0.117 mmol) of Noric acid and 33.0 mg of 2,4-bis (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine hydrochloride obtained from Preparation Example 127 Purification was carried out using (0.106 mmol) to give 13.0 mg (yield 20%) of the title compound.

¹ H NMR (CDCl ₃ )) δ 5.78-5.75 (1H, m), 5.06-4.80 (2H, m), 4.15-4.09 (1H, m), 3.98-3.85 (2H, m), 3.65-3.55 (1H , m), 3.46-3.44 (2H, m), 3.19-3.06 (3H, m), 2.87-2.76 (1H, m), 2.59-2.45 (3H, m), 2.04-1.94 (1H, m), 1.42 -1.40 (9H, m), 1.12-1.11 (3H, m)

Mass (m / e) 552 (M + 1)

Example  105: 1-{(2S) -2-amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -4-methyloxopyrrolidin-2-one

In the same manner as in Example 22, t-butyl {(1S) -3- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4-d obtained from Preparation Example 177 ] Pyrimidin-7 (6H) -yl] -1-[(4-methyl-2-oxopyrrolidin-1-yl) methyl] -3-oxopropyl} carbamate from 13.0 mg (0.0235 mmol) 10.0 mg (87% yield) of compound was obtained.

¹ H NMR (CD ₃ OD)) δ 5.05-4.97 (2H, m), 3.99 (1H, brs), 3.91-3.88 (2H, m), 3.77-3.73 (1H, m), 3.61-3.59 (1H, m), 3.48-3.45 (1H, m), 3.25 (1H, brs), 3.15 (2H, brs), 3.05-2.98 (1H, m), 2.89-2.79 (1H, m), 2.58-2.53 (2H, m), 2.12-2.07 (1 H, m), 1.17-1.63 (3 H, m).

Mass (m / e) 452 (M + 1)

Production Example  178: t-butyl {(1S) -3- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydropyri Degree [3,4-d] pyrimidine -7 (6H) -yl] -1-[(4- methyl -2- Oxopyrrolidine -1 day) methyl ] -3- Oxopro Phil} Carbamate  synthesis

In the same manner as in Production Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (4-methyl-2-oxopyrrolidin-1-yl) buta obtained from Production Example 168 2- (3-furyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d] from 35.0 mg (0.117 mmol) of Noric acid and Preparation 96 Separation and purification using 32.4 mg (0.117 mmol) of pyrimidine hydrochloride gave 26.0 mg (yield 44%) of the title compound.

¹ H NMR (CDCl ₃ )) δ 8.27 (1H, s), 7.50 (1H, s), 7.06 (1H, s), 5.76-5.70 (1H, m), 4.86 (1H, s), 4.80-4.69 ( 1H, m), 4.15-4.09 (1H, m), 3.91-3.88 (1H, m), 3.80-3.79 (1H, m), 3.67-3.42 (3H, m), 3.09-3.00 (3H, m), 2.87-2.79 (1H, m), 2.58-2.35 (3H, m), 2.02-1.97 (1H, m), 1.42-1.41 (9H, m), 1.11 (3H, d, J = 6.0 Hz).

Mass (m / e) 550 (M + 1)

Example  106: 1-{(2S) -2-amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydro Pyrido [3,4-d] pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -4-methylpyrrolidin-2-one

In the same manner as in Example 22, t-butyl {(1S) -3- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydropyrido [obtained from Preparation Example 178 [ 26.0 mg of 3,4-d] pyrimidin-7 (6H) -yl] -1-[(4-methyl-2-oxopyrrolidin-1-yl) methyl] -3-oxopropyl} carbamate 0.0471 mmol) to give 12.5 mg (54% yield) of the title compound.

¹ H NMR (CD ₃ OD)) δ 8.36 (1H, s), 7.65 (1H, s), 7.09 (1H, s), 4.91-4.84 (2H, m), 3.97 (1H, brs), 3.87 (2H , brs), 3.71-3.58 (3H, m), 3.14 (2H, brs), 3.04-2.99 (2H, m), 2.86-2.79 (1H, m), 2.60-2.51 (1H, m), 2.10-2.05 (2H, m), 1.22-1.16 (3H, m)

Mass (m / e) 450 (M + 1)

Production Example  179: t-butyl  [(1S) -3- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] -3-oxo- 1-{[2-oxo-5- ( Trifluoromethyl ) Piperidin-1-yl] methyl }profile] Carbamate  synthesis

In the same manner as in Production Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- [2-oxo-5- (trifluoromethyl) piperidine- obtained from Production Example 171 1, yl] butanoic acid 14.0 mg (0.038 mmol) and 2,4-bis (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d] obtained from Preparation Example 127 Separation and purification using 12.3 mg (0.038 mmol) of pyrimidine hydrochloride gave 18.0 mg (yield 76%) of the title compound.

¹ H NMR (CDCl ₃ )) δ 5.86-5.76 (1H, m), 5.04-4.91 (2H, m), 4.17 (1H, brs), 4.15-3.78 (2H, m), 3.68-3.44 (4H, m ), 3.22-3.10 (2H, m), 2.87-2.80 (1H, m), 2.60-2.45 (3H, m), 2.36-2.30 (1H, m), 2.07 (1H, brs), 1.88-1.84 (1H , m), 1.40-1.39 (9H, m)

Mass (m / e) 622 (M + 1)

Example  107: 1-{(2S) -2-amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -5- (trifluoromethyl) piperidin-2-one

T-butyl [(1S) -3- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4-d obtained in Preparation 178 in the same manner as in Example 22 ] Pyrimidin-7 (6H) -yl] -3-oxo-1-{[2-oxo-5- (trifluoromethyl) piperidin-1-yl] methyl} propyl] carbamate 18.0 mg ( 0.0289 mmol) to give 13.3 mg (83% yield) of the title compound.

¹ H NMR (CD ₃ OD)) δ 4.94-4.79 (2H, m), 3.89-3.86 (1H, m), 3.82-3.72 (2H, m), 3.66-3.52 (5H, m), 3.16-3.11 ( 1H, m), 3.04 (1H, brs), 2.94-2.73 (2H, m), 2.43-2.41 (2H, m), 2.08-2.02 (1H, m), 1.89-1.82 (1H, m)

Mass (m / e) 522 (M + 1)

Production Example  180: t-butyl {(1S) -3- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] -3-oxo-1-{[2-oxo-4- ( Trifluoromethyl ) Pyrrolidine -1 day] methyl }profile} Carbamate  synthesis

(3S) -3-[(t-butoxycarbonyl) amino] -4- [2-oxo-4- (trifluoromethyl) pyrrolidine- obtained from Production Example 172 in the same manner as in Production Example 45 2,4-bis (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d] obtained from 25.0 mg (0.061 mmol) of 1-yl] butanoic acid and Preparation Example 127 Separation and purification using 31.5 mg (0.061 mmol) of pyrimidine hydrochloride gave 21.0 mg (yield 41%) of the title compound.

¹ H NMR (CDCl ₃ )) δ 5.59 (1H, brs), 5.04-4.80 (2H, m), 4.17-4.11 (1H, m), 4.02-3.82 (2H, m), 3.75-3.66 (2H, m ), 3.63-3.58 (2H, m), 3.20-3.04 (3H, m), 2.86-2.75 (1H, m), 2.64-2.39 (3H, m), 1.42-1.40 (9H, m)

Mass (m / e) 608 (M + 1)

Example  108: 1-{(2S) -2-amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -4- (trifluoromethyl) pyrrolidin-2-one

T-butyl {(1S) -3- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4-d obtained from Production Example 180 in the same manner as in Example 22 ] Pyrimidin-7 (6H) -yl] -3-oxo-1-{[2-oxo-4- (trifluoromethyl) pyrrolidin-1-yl] methyl} propyl} carbamate 21.0 mg ( 0.0346 mmol) to give 18.2 mg (yield 96%) of the title compound.

¹ H NMR (CD ₃ OD)) δ 5.01-4.91 (2H, m), 3.98-3.76 (4H, m), 3.72-3.52 (4H, m), 3.22 (1H, brs), 3.11 (1H, m) , 3.03-2.94 (1H, m), 2.89-2.80 (1H, m), 2.73-2.65 (1H, m), 2.57-2.52 (1H, m)

Mass (m / e) 508 (M + 1)

Production Example  181: t-butyl [(1S) -3- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydropyri Degree [3,4-d] pyrimidine -7 (6H) -yl] -3-oxo-1-{[2-oxo-4- ( Trifluoromethyl ) Pyrrolidine -1 day] methyl }profile] Carbamate  synthesis

In the same manner as in Production Example 45, 3S) -3-[(t-butoxycarbonyl) amino] -4- [2-oxo-4- (trifluoromethyl) pyrrolidine-1 obtained from Production Example 172 -Yl] butanoic acid 25.0 mg (0.061 mmol) and 2- (3-furyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3, Separation and purification using 22.0 mg (0.061 mmol) of 4- d ] pyrimidine hydrochloride gave 30.0 mg (yield 82%) of the title compound.

¹ H NMR (CDCl ₃ )) δ 8.26 (1H, s), 7.49 (1H, d, J = 1.2 Hz), 7.04 (1H, d, J = 6.1 Hz), 5.61-5.55 (1H, m), 4.84 (2H, s), 4.76-4.68 (2H, m), 4.18 (1H, brs), 3.98 (1H, brs), 3.74-3.46 (4H, m), 3.10-2.98 (3H, m), 2.83-2.77 (1H, m), 2.63-2.50 (3H, m), 1.41-1.39 (9H, m)

Mass (m / e) 606 (M + 1)

Example  109: 1-{(2S) -2-amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydro Pyrido [3,4-d] pyrimidine -7 (6H) -yl] -4- Oxobutyl }-4-( Trifluoromethyl ) Pyrrolidine Synthesis of 2-one

T-butyl [(1S) -3- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydropyrido [obtained from Preparation Example 181 in the same manner as in Example 22; 3,4-d] pyrimidin-7 (6H) -yl] -3-oxo-1-{[2-oxo-4- (trifluoromethyl) pyrrolidin-1-yl] methyl} propyl] carr 34.7 mg (0.050 mmol) of bamate gave 24.7 mg (yield 92%) of the title compound.

¹ H NMR (CD ₃ OD)) δ 8.36 (1H, s), 7.65 (1H, s), 7.09 (1H, s), 4.92-4.90 (2H, m), 3.97-3.80 (4H, m), 3.70 -3.55 (4H, m), 3.15-3.10 (1H, m), 3.05-3.95 (2H, m), 2.85-2.72 (2H, m), 2.65-2.55 (1H, m)

Mass (m / e) 506 (M + 1)

Production Example  182: t-butyl {(1S) -3- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidin-7 (6H) -yl] -1-[(4- methyl -2- Oxopiperidine -1 day) methyl ] -3- Oxopro Phil} Carbamate  synthesis

In the same manner as in Production Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (4-methyl-2-oxopiperidin-1-yl) buta obtained from Production Example 174 20.0 mg (0.096 mmol) of Noric acid and 29.4 mg of 2,4-bis (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine hydrochloride from Preparation Example 127 (0.096 mmol) was used to separate and give 25 mg (yield 46%) of the title compound.

¹ H NMR (CDCl ₃ )) δ 6.00-5.94 (1H, m), 5.12-4.81 (2H, m), 4.19-4.05 (2H, m), 3.88 (2H, brs), 3.74-3.66 (1H, m ), 3.50-3.40 (3H, m), 3.30-3.15 (2H, m), 2.93-2.82 (1H, m), 2.58-2.37 (2H, m), 2.00-1.88 (3H, m), 1.46-1.44 (9H, m), 1.04-1.03 (3H, m)

Mass (m / e) 568 (M + 1)

Example  110: 1-{(2S) -2-amino-4- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -4-methyloxopiperidin-2-one

T-butyl {(1S) -3- [2,4-bis (trifluoromethyl) -5,8-dihydropyrido [3,4-d obtained from Preparation Example 182 in the same manner as in Example 22 ] Pyrimidin-7 (6H) -yl] -1-[(4-methyl-2-oxopiperidin-1-yl) methyl] -3-oxopropyl} carbamate from 25 mg (0.044 mmol) 21 mg (95% yield) of compound were obtained.

¹ H NMR (CD ₃ OD) δ 5.06-4.94 (2H, m), 4.00-3.86 (3H, m), 3.82-3.74 (1H, m), 3.61-3.59 (1H, m), 3.50-3.45 ( 2H, m), 3.26 (1H, brs), 3.15 (1H, brs), 3.05-2.98 (1H, m), 2.92-2.85 (1H, m), 2.47-2.44 (1H, m), 2.07-1.92 ( 3H, m), 1.57 (1H, brs), 1.05 (3H, d, J = 4.8 Hz)

Mass (m / e) 468 (M + 1)

Production Example  183: t-butyl  {(1S) -3- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydropyri Degree [3,4-d] pyrimidine -7 (6H) -yl] -1-[(4- methyl -2- Oxopiperidine -1 day) methyl ] -3- Oxopro  Phil} Carbamate  synthesis

In the same manner as in Preparation Example 45, (3S) -3-[(t-butoxycarbonyl) amino] -4- (4-methyl-2-oxopyrrolidin-1-yl) buta obtained from Preparation Example 174 3-0.0 mg (0.096 mmol) of Noric acid and 2- (3-furyl) -4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d] from Preparation Example 96 Separation and purification using 29.2 mg (0.096 mmol) of pyrimidine hydrochloride gave 43 mg (yield 80%) of the title compound.

¹ H NMR (CDCl ₃ )) δ 8.30 (1H, s), 7.54-7.53 (1H, m), 7.09 (1H, s), 5.92-5.90 (1H, m), 4.89 (1H, s), 4.80- 4.76 (1H, m), 4.23 (1H, brs), 3.94-3.79 (3H, m), 3.68-3.39 (4H, m), 3.11-3.03 (2H, m), 2.97-2.87 (1H, m), 2.57-2.47 (2H, m), 2.03-1.87 (3H, m), 1.46-1.44 (9H, m), 1.03 (3H, d, J = 5.6 Hz).

Mass (m / e) 566 (M + 1)

Example  111: 1-{(2S) -2-amino-4- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydro Pyrido [3,4-d] pyrimidine Synthesis of -7 (6H) -yl] -4-oxobutyl} -4-methylpiperidin-2-one

In the same manner as in Example 22, t-butyl {(1S) -3- [2- (3-furyl) -4- (trifluoromethyl) -5,8-dihydropyrido [obtained from Preparation Example 183 [ 3,4-d] pyrimidin-7 (6H) -yl] -1- [(4-methyl-2-oxopiperidin-1-yl) methyl] -3-oxopropyl} carbamate 43 mg ( 0.076 mmol) gave 37 mg (97% yield) of the title compound.

¹ H NMR (CD ₃ OD)) δ 8.24 (1H, d, J = 0.8 Hz), 7.57-7.52 (1H, m), 6.96 (1H, d, J = 1.2 Hz), 4.79-4.73 (2H, m ), 3.90-3.82 (4H, m), 3.77-3.71 (1H, m), 3.51-3.47 (1H, m), 3.43-3.31 (2H, m), 3.03 (1H, brs), 2.97-2.90 (1H , m), 2.84-2.75 (1H, m), 2.40-2.34 (1H, m), 2.01-1.80 (3H, m), 1.46 (1H, brs), 0.93 (3H, d, J = 4.0 Hz)

Mass (m / e) 466 (M + 1)

Preparation Example 184 Synthesis of 2- cyclobutyl -4- ( trifluoromethyl ) -5,6,7,8- tetrahydropyrido [3,4- d ] pyrimidine hydrochloride

(One) Of cyclobutanecarboxyimidamide  synthesis

Using 1.22 g (15 mmol) of cyclobutanecarbonitrile, 1.28 g (yield 87%) of the title compound were obtained in the same manner as in Production Example 58 (1).

NMR: ¹ H-NMR (CD ₃ OD) δ 3.50 (1H, m), 2.35 (4H, m), 2.1 (1H, m), 1.9 (1H, m)

(2) t- butyl-2-cyclobutyl-4- (trifluoromethyl) -5,8-dihydropyrido [3, 4- d] pyrimidin -7 (6 H) - Synthesis of carboxylate

500 mg (1.69 mmol) of t-butyl 3-oxo-4- (trifluoroacetyl) piperidine-1-carboxylate and 166 mg (1.69 mmol) of cyclobutanecarboxyimide obtained in step (1) To give 200 mg (yield 33%) of the title compound in the same manner as in Preparation 58 (2).

¹ H NMR (CDCl ₃ ) δ 4.69 (2H, s), 3.80 (1H, m), 3.70 (2H, t, J = 5.5 Hz), 2.97 (2H, br s), 2.45 (2H, m), 2.37 (2H, m), 2.08 (1H, m), 1.96 (1H, m), 1.49 (9H, s)

Mass (m / e) 358 (M + 1)

(3) Synthesis of 2- cyclobutyl -4- ( trifluoromethyl ) -5,6,7,8- tetrahydropyrido [3,4- d ] pyrimidine hydrochloride

(Trifluoromethyl) t- butyl-2-cyclobutyl-4 obtained in the above step (2) -5,8-dihydropyrido [3, 4- d] pyrimidin -7 (6 H) - carboxylic 200 mg (0.56 mmol) of carboxylate were used to obtain 100 mg (yield 69%) of the title compound in the same manner as in Preparation 58 (3).

¹ H NMR (CD ₃ OD) δ 4.47 (2H, s), 3.85 (1H, m), 3.59 (2H, t, J = 6.5 Hz), 3.29 (2H, br s), 2.4 (4H, m), 2.14 (1H, m), 1.95 (1H, m)

Mass (m / e) 258 (M + 1)

Production Example  185: t-butyl {(1S) -3- [2-cyclobutyl-4- (trifluoromethyl) -5,8-dihydropy Lido [3,4-d] pyrimidine -7 (6H)- yl ] -1-{[(5R) -5- methyl -2- Oxopiperidine -1 day] methyl } -3- jade Synthesis of Sopropyl} carbamate

57 mg of (3S) -3-[(t-butoxycarbonyl) amino] -4-[(5R) -5-methyl-2-oxopiperidin-1-yl] butanoic acid obtained from Preparation Example 51 (0.181 mmole) and 40.0 mg (0.164 of 2-cyclobutyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine hydrochloride obtained in Preparation Example 184 mmole) was used to obtain 65.0 mg (yield 65%) of the title compound in the same manner as in Preparation 45.

¹ H NMR (CDCl ₃ ) δ 5.87-5.83 (1H, m), 4.88-4.80 (1H, m), 4.75-4.64 (1H, m), 4.18-4.15 (1H, m), 3.90-3.74 (3H, m), 3.58-3.47 (2H, m), 3.36-3.33 (1H, m), 3.08-2.96 (3H, m), 2.86-2.80 (1H, m), 2.50-2.30 (8H, m), 2.10- 2.03 (1H, m), 2.00-1.90 (2H, m), 1.81-1.78 (1H, m), 1.43-1.39 (9H, m), 0.99-0.98 (3H, m)

Mass (m / e) 554 (M + 1)

Example 112: (5R) -1-{(2S) -2-amino-4- [2- cyclobutyl -4- ( trifluoromethyl ) -5,8 - dihydropyrido [3,4-d ] Synthesis of pyrimidin-7 (6H) -yl] -4-oxobutyl} -5-methylpiperidin-2-one

T-butyl {(1S) -3- [2-cyclobutyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 (obtained in Preparation Example 185) 6H) -yl] -1-{[(5R) -5-methyl-2-oxopiperidin-1-yl] methyl} -3-oxopropyl} carbamate 65.0 mg (0.117 mmole) In the same manner as in Example 22, 42.4 mg (yield 80%) of the title compound were obtained.

¹ H NMR (CD ₃ OD) δ 4.92-4.80 (2H, m), 3.91-3.83 (3H, m), 3.64-3.62 (1H, m), 3.55-3.41 (3H, m), 3.11-3.00 (3H , m), 2.78-2.73 (1H, m), 2.65-2.56 (1H, m), 2.52-2.31 (6H, m), 2.19-2.100 (1H, m), 2.03-1.94 (2H, m), 1.87 -1.84 (1H, m), 1.58-1.47 (1H, m), 1.04 (3H, d, J = 6.8 Hz)

Mass (m / e) 454 (M + 1)

Production Example  186: t-butyl {(1S) -3- [2-cyclobutyl-4- (trifluoromethyl) -5,8-dihydropy Lido [3,4-d] pyrimidine -7 (6H) -yl] -1-[(5,5- Difluoro -2- Oxopiperidine -1 day) methyl ] -3-Oxopropyl} carbamate

61 mg of (3S) -3-[(t-butoxycarbonyl) amino] -4- (5,5-difluoro-2-oxopiperidin-1-yl) butanoic acid obtained from Production Example 57 (0.181 mmole) and 40.0 mg (0.164 of 2-cyclobutyl-4- (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4-d] pyrimidine hydrochloride obtained in Preparation Example 194 mmole) was used to obtain 67.0 mg (yield 64%) of the title compound in the same manner as in Preparation 45.

¹ H NMR (CDCl ₃ ) δ 5.77 (1H, brs), 4.88-4.80 (1H, m), 4.73-4.65 (1H, m), 4.22-4.18 (1H, m), 3.88-3.68 (5H, m) , 3.59-3.48 (2H, m), 3.04-2.98 (2H, m), 2.84-2.79 (1H, m), 2.58 -2.50 (3H, m), 2.48-2.34 (4H, m), 2.30-2.20 ( 2H, m), 2.10-2.03 (1H, m), 1.98-1.92 (1H, m), 1.41-1.40 (9H, m)

Mass (m / e) 576 (M + 1-Boc)

Example  113: 1-{(2S) -2-amino-4- [2-cyclobutyl-4- (trifluoromethyl) -5,8-dihydropyri Degree [3,4-d] pyrimidine -7 (6H) -yl] -4- Oxobutyl } -5,5- Difluoropiperidine 2-on

T-butyl {(1S) -3- [2-cyclobutyl-4- (trifluoromethyl) -5,8-dihydropyrido [3,4-d] pyrimidine-7 (obtained in Preparation Example 186) 6H) -yl] -1-[(5,5-difluoro-2-oxopiperidin-1-yl) methyl] -3-oxopropyl} carbamate 67 mg (0.116 mmole) In the same manner as in Example 22, 43.9 mg (yield 79%) of the title compound were obtained.

¹ H NMR (CD ₃ OD) δ 4.91-4.79 (2H, m), 3.87-3.80 (5H, m), 3.53-3.48 (3H, m), 3.10-3.00 (2H, m), 2.73-2.32 (9H , m), 2.14-2.11 (1H, m), 1.99-1.96 (2H, m)

Mass (m / e) 476 (M + 1)

Experimental Example : DPP - IV  enzyme Inhibition  Measure

Cloning of Dipeptidyl Peptidase-IV (DPP-IV), known as serine protease, by a modification of the previously reported method (Tanaka T. et al, Proc. Natl. Acad. Sci. USA, (1994) 91, 3082-3086) By using Baculo-Virus, purification and activation were carried out, and drug efficacy was evaluated using the same. The cloned DPP-IV was expressed in Baculo-Virus, purified using a nickel column, and then obtained by dialysis. The degree of DPP-IV enzyme inhibition of the inhibitors synthesized using the fluorescent substrate Ac-Gly-Pro-AFC was measured. . In the enzyme reaction, various concentrations of inhibitors were reacted with 7.1 nM DPP-IV and 100 μm Ac-Gly-Pro-AFC in 25 ° C. buffer containing 50 mM HEPES (pH 7.4). IC ₅₀ values, the inhibitory constants of the inhibitors, were obtained by measuring the amount of inhibitor that inhibited the enzyme reaction by 50% by measuring the amount of fluorescence emitted after the enzymatic reaction for 1 hour by fluorescence spectroscopy. A spectra MAX GeminiXS fluorescence spectrometer, manufactured by Molecular Device, was used as the fluorescence spectrometer, and an excitation wavelength of 400 nm and an emission wavelength of 505 nm were used. The results for this are shown in Table 1 below.

TABLE 1

As described above, the novel compounds according to the present invention exert an effect on blood glucose by inhibiting the action of the DPP-IV enzyme to promote insulin secretion, diabetes mellitus caused by DPP-IV (particularly type II), It can be used for the treatment and prevention of obesity and the like.

Those skilled in the art to which the present invention pertains will be able to make various applications and modifications within the scope of the present invention based on the above contents.

Claims (6)

A compound of Formula 1 or a pharmaceutically acceptable salt thereof:

(One) Where A) A is a substituent of the formula (2);

(2) In which R ₁ Is hydrogen or C ₁ -C ₄ alkyl substituted with unsubstituted or halogen; X is -CH- or nitrogen; (B) B is selected from substituents of the formulas (8) to (11); i)

(8) Wherein R ₇ , R ₈ , R ₉ and R ₁₀ Are each independently hydrogen, halogen, or C ₁ -C ₄ alkyl substituted with unsubstituted or halogen; ii)

(9) Wherein R ₁₁ , R ₁₂ and R ₁₃ Are each independently hydrogen, halogen, or C ₁ -C ₄ alkyl substituted with unsubstituted or halogen; Y is oxygen, sulfur or SO ₂ ; iii)

10 Wherein R ₁₄ and R ₁₅ Are each independently hydrogen, halogen, or C ₁ -C ₄ alkyl unsubstituted or substituted with halogen; Z is -CH- or oxygen, and R ₁₄ is nothing when Z is oxygen; iv)

(11) In which R ₁₇ Is hydrogen, halogen, or C ₁ -C ₄ alkyl unsubstituted or substituted with halogen. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the halogen is fluorine when the C ₁ -C ₄ alkyl is substituted with halogen. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is an isomer represented by the following Chemical Formula 1a:

(1a) Wherein A and B are the same as defined in the formula (1). The compound or pharmaceutically acceptable salt thereof of claim 1, wherein the compound is selected from the group consisting of: 3- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -oxazolidin-2-one; 2.3- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -5-methyl-oxazolidin-2-one; 1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -piperidin-2-one; 1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -4-methyl-pyrrolidin-2-one; 1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -4,4-dimethyl-pyrrolidin-2-one; 1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -3-fluoro-pyrrolidin-2-one; 1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3- a ] pyrazine-7- Yl) -butyl] -pyrrolidin-2-one; 1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl]-3-fluoro-piperidin-2-one; 1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -4-methyl-1,5-dihydro-pyrrole-2-one; 1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -4-methyl-piperidin-2-one; 1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -5,5-difluoro-piperidin-2-one; 1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -5R-methyl-piperidin-2-one; 1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -4-trifluoromethyl-pyrrolidin-2-one; 1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -4-trifluoromethyl-piperidin-2-one; 1- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -5-trifluoromethyl-piperidin-2-one; 4- [2S-amino-4-oxo-4- (3-trifluoromethyl-5,6-dihydro-8H- [1,2,4] triazolo [4,3-a] pyrazine-7- Yl) -butyl] -6-methyl-morpholin-3-one; 1- [2S-amino-4-oxo-4- (3-trifluoromethyl-1,4,5,7-tetrahydro-pyrazolo [3,4- c ] pyridin-6-yl) -butyl] -Piperidin-2-one; A pharmaceutical composition comprising the compound of formula 1 according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier and used for the treatment or prevention of diabetes or obesity. delete